AU2021270095A1 - 1, 4, 5, 6-tetrahydropyrimidine-2-amine derivative - Google Patents

Abstract

The present invention provides a compound, or a pharmaceutically-acceptable salt thereof, represented by general formula (I) or (II) below [wherein A is a C

Description

221102_G2572WO English Translation (Final) clean copy

Description

Title of Invention:

1,4,5,6-TETRAHYDROPYRIMIDIN-2-AMINE DERIVATIVE

Technical Field

[0001] The present invention relates to a 1,4,5,6

tetrahydropyrimidin-2-amine derivative and a

pharmaceutical composition containing the same and

particularly relates to a 1,4,5,6-tetrahydropyrimidin-2

amine derivative for the prevention, alleviation and/or

remedy of a disease related to integrin av and a

pharmaceutical composition containing the same.

Background Art

[0002] In recent years, integrins have received attention

in terms of possessing cell adhesion or intracellular

signal transduction functions in response to

extracellular matrix information. The integrins are

proteins that are expressed on cell surface, and are

composed of a heterodimer of two subunits u and $ chains.

24 integrins form some subfamilies by combinations of 18

u chains and 8 $ chains. RGD integrin, one of the major

subfamilies, recognizes a ligand containing a RGD

(arginine-glycine-aspartic acid) motif in a protein

sequence. The RGD integrin includes 8 subtypes axvf1,

221102_G2572WO English Translation (Final) clean copy

avP3, avP5, avf6, avf8, axIIb3, a5f1, and u81 (Non

Patent Literature 1).

[0003] Integrin av is known to participate in various

diseases, and its inhibition is expected to have a

therapeutic effect on, for example, cardiovascular

disease, diabetic disease, neurodegenerative disease,

cancer disease, tumor metastasis, eye disease, autoimmune

disease, bone disease, and various fibroses (Non Patent

Literatures 2 to 6).

[0004] Transforming growth factor $ (TGF-) is known to

control cell proliferation, differentiation, or the like

and to participate in diseases such as fibrosis,

autoimmune disease, and cancer, and is secreted as an

inactive complex with latency-associated protein (LAP)

(Non Patent Literature 7). In research using cell, it

has been reported that RGD integrin such as integrin

axvpl, avP3, avP5, axvf6 and av8 activates latent TGF

(Non Patent Literatures 8 and 9).

[0005] Fibrosis, a pathological feature of many diseases,

is caused by the dysfunction of body's original ability

to repair injured tissues. Fibrosis brings about

excessive scarring that surpasses the wound healing

response of an important organ, and might cause

unrecoverable injury and final organ failure (Non Patent

Literature 10). In fibrosis, extracellular matrix is

mainly produced by activated fibroblasts

(myofibroblasts), and TGF- is known to participate in

221102_G2572WO English Translation (Final) clean copy

the activation of the fibroblasts (Non Patent Literature

11).

[0006] The expression of integrins also participates in

fibrosis. For example, the expression level of integrin

$5 or P6 markedly increases after tissue injury and plays

an important in vivo role in tissue fibrosis (Non Patent

Literatures 12 and 13). The increased expression level

of integrin $6 is also related to increase in the death

rate of fibrosis patients (Non Patent Literature 14).

[0007] The inhibition of integrins is known to exhibit

resistance to various fibroses. For example, integrin

$6-knockout mice inhibit the activation of TGF- and

exhibit resistance to various fibroses (Non Patent

Literatures 15 and 16). It has also been reported that

fibroblast-specific deficiency in integrin av similarly

exhibits resistance to various fibroses (Non Patent

Literatures 17 and 18).

[0008] For example, pirfenidone and nintedanib for

idiopathic pulmonary fibrosis (IPF) are used as

therapeutic drugs for fibrosis. However, any safe and

established therapeutic drug for various organ fibroses

has not yet been found. Thus, there is a demand for a

therapeutic drug for fibrosis that is effective for

various organs with reduced adverse reactions.

[0009] Research has been made so far on integrins

involved in the functional control of various cells or

221102_G2572WO English Translation (Final) clean copy

their inhibitors (Patent Literatures 1 to 8 and Non

Patent Literature 19).

Citation List

Patent Literature

[0010]

Patent Literature 1: WO 1997/008145

Patent Literature 2: WO 1999/044994

Patent Literature 3: WO 1999/052896

Patent Literature 4: WO 2000/051686

Patent Literature 5: WO 2004/060376

Patent Literature 6: WO 2014/015054

Patent Literature 7: US 2014/0051715

Patent Literature 8: WO 2017/117538

Non Patent Literature

[0011]

Non Patent Literature 1: Cell, 2002, 110 (6), 673-687

Non Patent Literature 2: Cellular and Molecular Life

Sciences, 2017, 74 (12), 2263-2282

Non Patent Literature 3: Pharmacology Research and

Perspectives, 2017, 5 (5), e00354

Non Patent Literature 4: Neurobiology of Aging, 2008, 29

(10), 1485-1493

Non Patent Literature 5: Angewandte Chemie International

Edition in English, 2018, 57 (13), 3298-3321

Non Patent Literature 6: Clinical & Experimental

Metastasis, 2003, 20, 203-213

221102_G2572WO English Translation (Final) clean copy

Non Patent Literature 7: Cold Spring Harbor Perspectives

in Biology, 2016, 8 (5), a021873

Non Patent Literature 8: Cold Spring Harbor Perspectives

in Biology, 2011, 3 (11), a005017

Non Patent Literature 9: Science Translational Medicine,

2015, 7 (288), 288ra79

Non Patent Literature 10: Molecular Aspects of Medicine,

2019, 65, 2-15

Non Patent Literature 11: Nature Reviews Nephrology,

2016, 12 (6), 325-338

Non Patent Literature 12: Journal of Hepatology, 2008, 48

(3), 453-464

Non Patent Literature 13: The American Journal of

Pathology, 2004, 164 (4), 1275-1292

Non Patent Literature 14: European Respiratory Journal,

2015, 46 (2), 486-494

Non Patent Literature 15: The American Journal of

Pathology, 2003, 163 (4), 1261-1273

Non Patent Literature 16: Cell, 1999, 96 (3), 319-328

Non Patent Literature 17: Nature Medicine, 2013, 19 (12),

1617-1624

Non Patent Literature 18: Nature Communications, 2017, 8

(1), 1118

Non Patent Literature 19: Biochemical Pharmacology, 2016,

117, 88-96

Summary of Invention

221102_G2572WO English Translation (Final) clean copy

Technical Problem

[0012] The present invention relates to the provision of

a novel compound useful in the prevention, alleviation

and/or remedy of a disease related to integrin av and a

pharmaceutical composition containing the same.

Solution to Problem

[0013] The present inventors have conducted diligent

studies on compounds having integrin av inhibitory

activity and consequently found that a series of 1,4,5,6

tetrahydropyrimidin-2-amine derivatives having an

intramolecular indazole structure, or pharmaceutically

acceptable salts thereof have excellent integrin av

(av$l, av$6, etc.) inhibitory activity, excellent

pharmacokinetic characteristics or excellent safety. The

1,4,5,6-tetrahydropyrimidin-2-amine derivative according

to the present invention or a pharmaceutically acceptable

salt thereof can be useful in the prevention, alleviation

and/or remedy of a disease related to integrin av,

preferably the prevention, alleviation and/or remedy of

fibrosis.

[0014] Specifically, the present invention is as follows.

[1] A compound represented by the following general

formula (I) or (II) or a pharmaceutically acceptable salt

thereof:

221102_G2572WO English Translation (Final) clean copy

Y Y

HN N O HN N O HN N N C2R HN N CO 2 R 1 0 A 0 O A R 1x/ R N-NH HN-N

(I) (II) wherein

A is a C6-C10 aryl group or a heteroaryl group,

wherein at least one hydrogen atom of the aryl group or

the heteroaryl group is optionally replaced with a

substituent selected from the group consisting of a

halogen atom, a hydroxy group, a C1-C6 alkyl group, a C1

C6 haloalkyl group, a C2-C6 alkenyl group, a C2-C6 alkynyl

group, a C1-C6 alkoxy group, a C1-C6 haloalkoxy group, a

C3-C6 cycloalkyl group, a C3-C6 cycloalkenyl group, a C3-C6

cycloalkoxy group, a heterocyclyl group, a heteroaryl

group optionally substituted by a C1-C6 alkyl group, a

cyano group, a carboxyl group, a carbamoyl group, a C1-C6

alkoxycarbonyl group, a C1-C6 alkylsulfanyl group, and a

C1-C6 alkylsulfonyl group,

R is a hydrogen atom or a C1-C6 alkyl group,

R' is a hydrogen atom or a halogen atom, and

Y is a hydrogen atom, a fluorine atom or a hydroxy

group.

[2] A compound represented by the following general

formula (I) or a pharmaceutically acceptable salt

thereof:

221102_G2572WO English Translation (Final) clean copy

Y

HN N HN N CO 2 R

R 1 H0 A N-NH

(I) wherein

A is a C6-C10 aryl group or a heteroaryl group,

wherein at least one hydrogen atom of the aryl group or

the heteroaryl group is optionally replaced with a

substituent selected from the group consisting of a

halogen atom, a hydroxy group, a C1-C6 alkyl group, a C1

C6 haloalkyl group, a C2-C6 alkenyl group, a C2-C6 alkynyl

group, a C1-C6 alkoxy group, a C1-C6 haloalkoxy group, a

C3-C6 cycloalkyl group, a C3-C6 cycloalkenyl group, a C3-C6

cycloalkoxy group, a heterocyclyl group, a heteroaryl

group optionally substituted by a C1-C6 alkyl group, a

cyano group, a carboxyl group, a carbamoyl group, a C1-C6

alkoxycarbonyl group, a C1-C6 alkylsulfanyl group, and a

C1-C6 alkylsulfonyl group,

R is a hydrogen atom or a C1-C6 alkyl group,

R' is a hydrogen atom or a halogen atom, and

Y is a hydrogen atom, a fluorine atom or a hydroxy

group.

[3] A compound represented by the following general

formula (II) or a pharmaceutically acceptable salt

thereof:

221102_G2572WO English Translation (Final) clean copy

Y

HN N HN O' N N CO2 R 0 A

HN-N

wherein

A is a C6-C10 aryl group or a heteroaryl group,

wherein at least one hydrogen atom of the aryl group or

the heteroaryl group is optionally replaced with a

substituent selected from the group consisting of a

halogen atom, a hydroxy group, a C1-C6 alkyl group, a C1

C6 haloalkyl group, a C2-C6 alkenyl group, a C2-C6 alkynyl

group, a C1-C6 alkoxy group, a C1-C6 haloalkoxy group, a

C3-C6 cycloalkyl group, a C3-C6 cycloalkenyl group, a C3-C6

cycloalkoxy group, a heterocyclyl group, a heteroaryl

group optionally substituted by a C1-C6 alkyl group, a

cyano group, a carboxyl group, a carbamoyl group, a C1-C6

alkoxycarbonyl group, a C1-C6 alkylsulfanyl group, and a

C1-C6 alkylsulfonyl group,

R is a hydrogen atom or a C1-C6 alkyl group,

R' is a hydrogen atom or a halogen atom, and

Y is a hydrogen atom, a fluorine atom or a hydroxy

group.

[4] The compound according to any one of [1] to [3] or a

pharmaceutically acceptable salt thereof, wherein A is a

phenyl group, wherein

221102_G2572WO English Translation (Final) clean copy

at least one hydrogen atom of the phenyl group is

optionally replaced with a substituent selected from the

group consisting of a halogen atom, a hydroxy group, a

C1-C6 alkyl group, a C1-C6 haloalkyl group, a C2-C6 alkenyl

group, a C2-C6 alkynyl group, a C1-C alkoxy group, a C1-C6

haloalkoxy group, a C3-C6 cycloalkyl group, a C3-C6

cycloalkenyl group, a C3-C6 cycloalkoxy group, a

heterocyclyl group, a heteroaryl group optionally

substituted by a C1-C alkyl group, a cyano group, a

carboxyl group, a carbamoyl group, a C1-C6 alkoxycarbonyl

group, a C1-C6 alkylsulfanyl group, and a C1-C6

alkylsulfonyl group.

[5] The compound according to any one of [1] to [4] or a

pharmaceutically acceptable salt thereof, wherein A is a

phenyl group, wherein

at least one hydrogen atom of the phenyl group is

optionally replaced with a substituent selected from the

group consisting of a halogen atom, a hydroxy group, a

C1-C6 alkyl group, a C1-C6 haloalkyl group, a C2-C6 alkenyl

group, a C1-C6 alkoxy group, a C1-C6 haloalkoxy group, a

C3-C6 cycloalkyl group, a C3-C6 cycloalkenyl group, a C3-C6

cycloalkoxy group, a heterocyclyl group, a heteroaryl

group optionally substituted by a C1-C6 alkyl group, a

cyano group, a carboxyl group, a carbamoyl group, a C1-C6

alkoxycarbonyl group, a C1-C6 alkylsulfanyl group, and a

C1-C6 alkylsulfonyl group.

221102_G2572WO English Translation (Final) clean copy

[6] The compound according to any one of [1] to [5] or a

pharmaceutically acceptable salt thereof, wherein A is a

phenyl group, wherein

at least one hydrogen atom of the phenyl group is

optionally replaced with a substituent selected from the

group consisting of a halogen atom, a C1-C6 alkyl group,

a C1-C6 haloalkyl group, a C1-C6 alkoxy group, a C1-C6

haloalkoxy group, a C3-C6 cycloalkyl group, a C3-C6

cycloalkoxy group, a heterocyclyl group, and a heteroaryl

group optionally substituted by a C1-C6 alkyl group.

[7] The compound according to any one of [1] to [6] or a

pharmaceutically acceptable salt thereof, wherein Y is a

fluorine atom.

[8] The compound according to any one of [1] to [7] or a

pharmaceutically acceptable salt thereof, wherein

A is a group represented by the following formula

(i): *

R5 4R

0) wherein

R 2 is a hydrogen atom or a halogen atom,

R 3 is a hydrogen atom, a halogen atom, a C1-C6 alkyl

group, a C1-C6 haloalkyl group, a C1-C6 alkoxy group, a

C1-C6 haloalkoxy group, a C3-C6 cycloalkyl group, a C3-C6

221102_G2572WO English Translation (Final) clean copy

cycloalkoxy group, a heterocyclyl group, or a heteroaryl

group optionally substituted by a C1-C6 alkyl group,

R4 is a hydrogen atom, a halogen atom, a C1-C6 alkyl

group, a C1-C6 haloalkyl group, a C1-C6 alkoxy group, or a

C1-C6 haloalkoxy group,

R5 is a hydrogen atom, a halogen atom, a C1-C6 alkyl

group, a C1-C6 haloalkyl group, a C1-C6 alkoxy group, a

C1-C6 haloalkoxy group, or a heteroaryl group optionally

substituted by a C1-C6 alkyl group, and

R 6 is a hydrogen atom or a halogen atom.

[9] The compound according to [8] or a pharmaceutically

acceptable salt thereof, wherein

R 2 is a hydrogen atom,

R3 is a hydrogen atom, a halogen atom, a C1-C6 alkyl

group, a C1-C6 haloalkyl group, a C1-C6 alkoxy group, a

C1-C6 haloalkoxy group, or a heteroaryl group optionally

substituted by a C1-C6 alkyl group,

R 4 is a hydrogen atom or a halogen atom,

R5 is a hydrogen atom, a halogen atom, a C1-C6 alkyl

group, a C1-C6 haloalkyl group, a C1-C6 alkoxy group, or a

C1-C6 haloalkoxy group, and

R 6 is a hydrogen atom or a halogen atom.

[10] The compound according to [1] or a pharmaceutically

acceptable salt thereof, wherein the compound is selected

from the group consisting of

221102_G2572WO English Translation (Final) clean copy

(3S)-3-(3-chloro-5-(trifluoromethyl)phenyl)-3-(2-(4

((5-fluoro-1,4,5,6-tetrahydropyrimidin-2-yl)amino)-1H

indazole-6-carboxamido)acetamido)propanoic acid,

(3S)-3-(3-bromo-5-(trifluoromethyl)phenyl)-3-(2-(4

((5-fluoro-1,4,5,6-tetrahydropyrimidin-2-yl)amino)-1H

indazole-6-carboxamido)acetamido)propanoic acid,

(3S)-3-(2-(4-((5-fluoro-1,4,5,6-tetrahydropyrimidin

2-yl)amino)-1H-indazole-6-carboxamido)acetamido)-3-(3

iodo-5-(trifluoromethyl)phenyl)propanoic acid,

(3S)-3-(2-(4-((5-fluoro-1,4,5,6-tetrahydropyrimidin

2-yl)amino)-1H-indazole-6-carboxamido)acetamido)-3-(3

methyl-5-(trifluoromethyl)phenyl)propanoic acid,

(3S)-3-(2-(4-((5-fluoro-1,4,5,6-tetrahydropyrimidin

2-yl)amino)-1H-indazole-6-carboxamido)acetamido)-3-(3

methoxy-5-(trifluoromethyl)phenyl)propanoic acid,

(3S)-3-(2-(4-((5-fluoro-1,4,5,6-tetrahydropyrimidin

2-yl)amino)-1H-indazole-6-carboxamido)acetamido)-3-(3

fluoro-5-(trifluoromethyl)phenyl)propanoic acid,

(3S)-3-(3,5-bis(trifluoromethyl)phenyl)-3-(2-(4-((5

fluoro-1,4,5,6-tetrahydropyrimidin-2-yl)amino)-1H

indazole-6-carboxamido)acetamido)propanoic acid,

(3S)-3-(3-(1H-pyrazol-1-yl)-5

(trifluoromethyl)phenyl)-3-(2-(4-((5-fluoro-1,4,5,6

tetrahydropyrimidin-2-yl)amino)-1H-indazole-6

carboxamido)acetamido)propanoic acid,

221102_G2572WO English Translation (Final) clean copy

(3S)-3-(2-(4-((5-fluoro-1,4,5,6-tetrahydropyrimidin

2-yl)amino)-1H-indazole-6-carboxamido)acetamido)-3-(2

fluoro-3-(trifluoromethyl)phenyl)propanoic acid,

(3S)-3-(2-chloro-3-(trifluoromethyl)phenyl)-3-(2-(4

((5-fluoro-1,4,5,6-tetrahydropyrimidin-2-yl)amino)-1H

indazole-6-carboxamido)acetamido)propanoic acid,

(3S)-3-(2-(4-((5-fluoro-1,4,5,6-tetrahydropyrimidin

2-yl)amino)-1H-indazole-6-carboxamido)acetamido)-3-(2

fluoro-5-(trifluoromethyl)phenyl)propanoic acid,

(3S)-3-(2-chloro-5-(trifluoromethyl)phenyl)-3-(2-(4

((5-fluoro-1,4,5,6-tetrahydropyrimidin-2-yl)amino)-1H

indazole-6-carboxamido)acetamido)propanoic acid,

(3S)-3-(2-(4-((5-fluoro-1,4,5,6-tetrahydropyrimidin

2-yl)amino)-1H-indazole-6-carboxamido)acetamido)-3-(4

fluoro-3-(trifluoromethyl)phenyl)propanoic acid,

(3S)-3-(2-(4-((5-fluoro-1,4,5,6-tetrahydropyrimidin

2-yl)amino)-1H-indazole-6-carboxamido)acetamido)-3-(4

methyl-3-(trifluoromethyl)phenyl)propanoic acid,

(3S)-3-(3-chloro-4-fluoro-5

(trifluoromethyl)phenyl)-3-(2-(4-((5-fluoro-1,4,5,6

tetrahydropyrimidin-2-yl)amino)-1H-indazole-6

carboxamido)acetamido)propanoic acid,

(3S)-3-(3-bromo-4-methoxyphenyl)-3-(2-(4-((5-fluoro

1,4,5,6-tetrahydropyrimidin-2-yl)amino)-1H-indazole-6

carboxamido)acetamido)propanoic acid,

221102_G2572WO English Translation (Final) clean copy

(3S)-3-(3,5-dichlorophenyl)-3-(2-(4-((5-fluoro

1,4,5,6-tetrahydropyrimidin-2-yl)amino)-1H-indazole-6

carboxamido)acetamido)propanoic acid,

(3S)-3-(3-bromo-5-chlorophenyl)-3-(2-(4-((5-fluoro

1,4,5,6-tetrahydropyrimidin-2-yl)amino)-1H-indazole-6

carboxamido)acetamido)propanoic acid,

(3S)-3-(3,5-dibromophenyl)-3-(2-(4-((5-fluoro

1,4,5,6-tetrahydropyrimidin-2-yl)amino)-1H-indazole-6

carboxamido)acetamido)propanoic acid,

(3S)-3-(3-bromo-5-iodophenyl)-3-(2-(4-((5-fluoro

1,4,5,6-tetrahydropyrimidin-2-yl)amino)-1H-indazole-6

carboxamido)acetamido)propanoic acid,

(3S)-3-(3-chloro-5-iodophenyl)-3-(2-(4-((5-fluoro

1,4,5,6-tetrahydropyrimidin-2-yl)amino)-1H-indazole-6

carboxamido)acetamido)propanoic acid,

(3S)-3-(5-chloro-2-fluorophenyl)-3-(2-(4-((5-fluoro

1,4,5,6-tetrahydropyrimidin-2-yl)amino)-1H-indazole-6

carboxamido)acetamido)propanoic acid,

(3S)-3-(5-bromo-2-fluorophenyl)-3-(2-(4-((5-fluoro

1,4,5,6-tetrahydropyrimidin-2-yl)amino)-1H-indazole-6

carboxamido)acetamido)propanoic acid,

(3S)-3-(3-(difluoromethoxy)-5

(trifluoromethyl)phenyl)-3-(2-(4-((5-fluoro-1,4,5,6

tetrahydropyrimidin-2-yl)amino)-1H-indazole-6

carboxamido)acetamido)propanoic acid,

221102_G2572WO English Translation (Final) clean copy

(3S)-3-(3-chloro-5-(difluoromethoxy)phenyl)-3-(2-(4

((5-fluoro-1,4,5,6-tetrahydropyrimidin-2-yl)amino)-1H

indazole-6-carboxamido)acetamido)propanoic acid,

(3S)-3-(3-bromo-5-(difluoromethoxy)phenyl)-3-(2-(4

((5-fluoro-1,4,5,6-tetrahydropyrimidin-2-yl)amino)-1H

indazole-6-carboxamido)acetamido)propanoic acid,

(3S)-3-(3-(difluoromethoxy)-4-fluorophenyl)-3-(2-(4

((5-fluoro-1,4,5,6-tetrahydropyrimidin-2-yl)amino)-1H

indazole-6-carboxamido)acetamido)propanoic acid,

(3S)-3-(5-(difluoromethoxy)-2-fluorophenyl)-3-(2-(4

((5-fluoro-1,4,5,6-tetrahydropyrimidin-2-yl)amino)-1H

indazole-6-carboxamido)acetamido)propanoic acid,

(3S)-3-(3-(difluoromethoxy)-5-(1H-pyrazol-1

yl)phenyl)-3-(2-(4-((5-fluoro-1,4,5,6

tetrahydropyrimidin-2-yl)amino)-1H-indazole-6

carboxamido)acetamido)propanoic acid,

(3S)-3-(3,5-bis(difluoromethoxy)phenyl)-3-(2-(4-((5

fluoro-1,4,5,6-tetrahydropyrimidin-2-yl)amino)-1H

indazole-6-carboxamido)acetamido)propanoic acid,

(3S)-3-(3-chloro-5-(trifluoromethoxy)phenyl)-3-(2

(4-((5-fluoro-1,4,5,6-tetrahydropyrimidin-2-yl)amino)-1H

indazole-6-carboxamido)acetamido)propanoic acid,

(3S)-3-(3-bromo-5-(trifluoromethoxy)phenyl)-3-(2-(4

((5-fluoro-1,4,5,6-tetrahydropyrimidin-2-yl)amino)-1H

indazole-6-carboxamido)acetamido)propanoic acid,

221102_G2572WO English Translation (Final) clean copy

(3S)-3-(2-(4-((5-fluoro-1,4,5,6-tetrahydropyrimidin

2-yl)amino)-1H-indazole-6-carboxamido)acetamido)-3-(2

fluoro-5-(trifluoromethoxy)phenyl)propanoic acid,

(3S)-3-(2-(4-((5-fluoro-1,4,5,6-tetrahydropyrimidin

2-yl)amino)-1H-indazole-6-carboxamido)acetamido)-3-(4

fluoro-3-(trifluoromethoxy)phenyl)propanoic acid,

(3S)-3-(2-(4-((5-fluoro-1,4,5,6-tetrahydropyrimidin

2-yl)amino)-1H-indazole-6-carboxamido)acetamido)-3-(3

(trifluoromethyl)phenyl)propanoic acid,

(3S)-3-(2-(4-((5-fluoro-1,4,5,6-tetrahydropyrimidin

2-yl)amino)-1H-indazole-6-carboxamido)acetamido)-3-(3

(trifluoromethoxy)phenyl)propanoic acid,

(3S)-3-(3-(difluoromethoxy)phenyl)-3-(2-(4-((5

fluoro-1,4,5,6-tetrahydropyrimidin-2-yl)amino)-1H

indazole-6-carboxamido)acetamido)propanoic acid,

(3S)-3-(3-(difluoromethyl)phenyl)-3-(2-(4-((5

fluoro-1,4,5,6-tetrahydropyrimidin-2-yl)amino)-1H

indazole-6-carboxamido)acetamido)propanoic acid,

(3S)-3-(3-cyclopropylphenyl)-3-(2-(4-((5-fluoro

1,4,5,6-tetrahydropyrimidin-2-yl)amino)-1H-indazole-6

carboxamido)acetamido)propanoic acid,

(3S)-3-(3-cyclopropoxyphenyl)-3-(2-(4-((5-fluoro

1,4,5,6-tetrahydropyrimidin-2-yl)amino)-1H-indazole-6

carboxamido)acetamido)propanoic acid,

(3S)-3-(3-chlorophenyl)-3-(2-(4-((5-fluoro-1,4,5,6

tetrahydropyrimidin-2-yl)amino)-1H-indazole-6

carboxamido)acetamido)propanoic acid,

221102_G2572WO English Translation (Final) clean copy

(3S)-3-(3-bromophenyl)-3-(2-(4-((5-fluoro-1,4,5,6

tetrahydropyrimidin-2-yl)amino)-1H-indazole-6

carboxamido)acetamido)propanoic acid,

(3S)-3-(3-(1H-pyrazol-1-yl)phenyl)-3-(2-(4-((5

fluoro-1,4,5,6-tetrahydropyrimidin-2-yl)amino)-1H

indazole-6-carboxamido)acetamido)propanoic acid,

(3S)-3-(3-(3,5-dimethyl-1H-pyrazol-1-yl)phenyl)-3

(2-(4-((5-fluoro-1,4,5,6-tetrahydropyrimidin-2-yl)amino)

1H-indazole-6-carboxamido)acetamido)propanoic acid,

(3S)-3-(2-(4-((5-fluoro-1,4,5,6-tetrahydropyrimidin

2-yl)amino)-1H-indazole-6-carboxamido)acetamido)-3-(3

morpholinophenyl)propanoic acid,

(3S)-3-(4-(difluoromethoxy)phenyl)-3-(2-(4-((5

fluoro-1,4,5,6-tetrahydropyrimidin-2-yl)amino)-1H

indazole-6-carboxamido)acetamido)propanoic acid,

(3S)-3-(2-(4-((5-fluoro-1,4,5,6-tetrahydropyrimidin

2-yl)amino)-1H-indazole-6-carboxamido)acetamido)-3-(4

(trifluoromethyl)phenyl)propanoic acid,

(3S)-3-(3-chloro-5-(trifluoromethyl)phenyl)-3-(2-(3

fluoro-4-((5-fluoro-1,4,5,6-tetrahydropyrimidin-2

yl)amino)-1H-indazole-6-carboxamido)acetamido)propanoic

acid,

(3S)-3-(2-(3-chloro-4-((5-fluoro-1,4,5,6

tetrahydropyrimidin-2-yl)amino)-1H-indazole-6

carboxamido)acetamido)-3-(3-chloro-5

(trifluoromethyl)phenyl)propanoic acid,

221102_G2572WO English Translation (Final) clean copy

(3S)-3-(3-chloro-5-(trifluoromethyl)phenyl)-3-(2-(4

((5-hydroxy-1,4,5,6-tetrahydropyrimidin-2-yl)amino)-1H

indazole-6-carboxamido)acetamido)propanoic acid,

(S)-3-(3-chloro-5-(trifluoromethyl)phenyl)-3-(2-(4

((1,4,5,6-tetrahydropyrimidin-2-yl)amino)-1H-indazole-6

carboxamido)acetamido)propanoic acid,

(3S)-3-(3-chloro-5-(trifluoromethyl)phenyl)-3-(2-(6

((5-fluoro-1,4,5,6-tetrahydropyrimidin-2-yl)amino)-1H

indazole-4-carboxamido)acetamido)propanoic acid,

(3S)-3-(3-bromo-5-(trifluoromethyl)phenyl)-3-(2-(6

((5-fluoro-1,4,5,6-tetrahydropyrimidin-2-yl)amino)-1H

indazole-4-carboxamido)acetamido)propanoic acid,

(3S)-3-(2-(6-((5-fluoro-1,4,5,6-tetrahydropyrimidin

2-yl)amino)-1H-indazole-4-carboxamido)acetamido)-3-(3

iodo-5-(trifluoromethyl)phenyl)propanoic acid,

(3S)-3-(2-(6-((5-fluoro-1,4,5,6-tetrahydropyrimidin

2-yl)amino)-1H-indazole-4-carboxamido)acetamido)-3-(4

fluoro-3-(trifluoromethyl)phenyl)propanoic acid, and

(3S)-3-(2-(6-((5-fluoro-1,4,5,6-tetrahydropyrimidin

2-yl)amino)-1H-indazole-4-carboxamido)acetamido)-3-(3

(trifluoromethyl)phenyl)propanoic acid.

[0015] In another embodiment, the present invention

relates to a pharmaceutical composition comprising a

compound according to any one of [1] to [10] or a

pharmaceutically acceptable salt thereof, and

in an embodiment of the pharmaceutical composition,

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relates to a pharmaceutical composition for

preventing, alleviating and/or treating a disease related

to integrin av or a disease that is improved by

inhibiting integrin av, or

a pharmaceutical composition for treating fibrosis.

[0016] In an alternative embodiment, the present

invention relates to a pharmaceutical composition, more

preferably a pharmaceutical composition for the treatment

of fibrosis, i.e., the prevention, alleviation and/or

remedy of fibrosis, comprising a compound according to

any one of [1] to [10] or a pharmaceutically acceptable

salt thereof.

[0017] In an alternative embodiment, the present

invention relates to a method for the treatment of a

disease related to integrin av or a disease that is

improved by inhibiting integrin av, for example,

fibrosis, comprising administering a compound according

to any one of [1] to [10] or a pharmaceutically

acceptable salt thereof to a subject.

[0018] In an alternative embodiment, the present

invention relates to use of a compound according to any

one of [1] to [10] or a pharmaceutically acceptable salt

thereof in the treatment of a disease related to integrin

axv or a disease that is improved by inhibiting integrin

axv, for example, fibrosis.

[0019] In an alternative embodiment, the present

invention relates to the compound according to any one of

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[1] to [10] or a pharmaceutically acceptable salt thereof

for use in the treatment of a disease related to integrin

axv or a disease that is improved by inhibiting integrin

axv, for example, fibrosis.

[0020] In an alternative embodiment, the present

invention relates to use of a compound according to any

one of [1] to [10] or a pharmaceutically acceptable salt

thereof in the production of a medicament for the

treatment of a disease related to integrin av or a

disease that is improved by inhibiting integrin av, for

example, fibrosis.

[0021] In an alternative embodiment, the present

invention relates to an intermediate of a compound

according to any one of [1] to [10] or a pharmaceutically

acceptable salt thereof.

[0022] In an alternative embodiment, the present

invention relates to a method for producing a compound

according to any one of [1] to [10] or a pharmaceutically

acceptable salt thereof.

Advantageous Effects of Invention

[0023] The present invention provides a novel compound

and a method for synthesizing the compound. Another

aspect of the present invention provides a pharmaceutical

composition for the prevention, alleviation and/or remedy

of a disease related to at least any integrin av (e.g.,

fibrosis), comprising the compound, the compound for

221102_G2572WO English Translation (Final) clean copy

preventing, alleviating and/or treating the disease, or a

method for preventing, alleviating and/or treating the

disease with the compound. An alternative aspect of the

present invention provides a novel intermediate for

synthesizing the compound.

Description of Embodiments

[0024] <Definition>

In the present specification, various substituents

are as follows.

The "C6-C10 aryl group" means a monocyclic or

dicyclic monovalent aromatic hydrocarbon group having 6

to 10 ring-forming carbon atoms. Examples of the aryl

group include phenyl and naphthyl.

[0025] The "heteroaryl group" means a monovalent aromatic

heterocyclic group containing at least one heteroatom

selected from a nitrogen atom, an oxygen atom and a

sulfur atom and is preferably a monovalent aromatic

heterocyclic group having 5 to 10 ring-forming atoms.

Examples of the heteroaryl group include: monocyclic

heteroaryl groups such as pyrrolyl, furyl, thienyl,

pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl,

isothiazolyl, triazolyl, oxadiazolyl, thiadiazolyl,

tetrazolyl, pyranyl, pyridyl, pyridazinyl, pyrimidinyl,

and pyrazinyl; and dicyclic heteroaryl groups such as

indolyl, indazolyl, benzotriazolyl, benzofuranyl,

221102_G2572WO English Translation (Final) clean copy

benzimidazolyl, benzothiophenyl, benzisoxazolyl,

benzopyranyl, benzothienyl, quinolyl, and isoquinolyl.

[0026] The "halogen" or the "halo" means a halogen atom.

Examples thereof include a fluorine atom (fluoro), a

chlorine atom (chloro), a bromine atom (bromo) and an

iodine atom (iodo).

[0027] The "C1-C6 alkyl group" means an alkyl group having

1 to 6 carbon atoms, and the alkyl group may be a linear

alkyl group or may be a branched alkyl group. Examples

of the alkyl group include methyl, ethyl, n-propyl,

isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n

pentyl, isopentyl, neopentyl, tert-pentyl, n-hexyl,

isohexyl, neohexyl, and tert-hexyl. The alkyl group may

be a C1-C4 alkyl group.

[0028] The "C1-C6 haloalkyl group" means a group in which

at least one hydrogen of the "C1-C6 alkyl group" is

replaced with a halogen atom. The haloalkyl group may be

a linear haloalkyl group or may be a branched haloalkyl

group. Examples of the haloalkyl group include

fluoromethyl, chloromethyl, bromomethyl, iodomethyl,

difluoromethyl, dichloromethyl, dibromomethyl,

diiodomethyl, trifluoromethyl, trichloromethyl,

tribromomethyl, triiodomethyl, 2-fluoroethyl, 2

chloroethyl, 2-bromoethyl, 2-iodoethyl, 2,2

difluoroethyl, 2,2-dichloroethyl, 2,2-dibromoethyl, 2,2

diiodoethyl, 2,2,2-trifluoroethyl, 2,2,2-trichloroethyl,

2,2,2-tribromoethyl, 2,2,2-triiodoethyl, 3-fluoropropyl,

221102_G2572WO English Translation (Final) clean copy

3-chloropropyl, 3-bromopropyl, 3-iodopropyl, 4

fluorobutyl, 4-chlorobutyl, 4-bromobutyl, 4-iodobutyl, 5

fluoropentyl, 5-chloropentyl, 5-bromopentyl, 5

iodopentyl, 6-fluorohexyl, 6-chlorohexyl, 6-bromohexyl,

and 6-iodohexyl. The haloalkyl group may be a C1-C4

haloalkyl group.

[0029] The "C2-C6 alkenyl group" means an alkenyl group

having 2 to 6 carbon atoms, and the alkenyl group may be

a linear alkenyl group or may be a branched alkenyl

group. Examples of the alkenyl group include vinyl,

allyl, 1-propenyl, 2-propenyl, 1-butenyl, 2-butenyl, 3

butenyl, 1-methyl-1-propenyl, 1-methyl-2-propenyl, 2

methyl-1-propenyl, 2-methyl-2-propenyl, 1-pentenyl, 2

pentenyl, 3-pentenyl, 4-pentenyl, 1-methyl-2-butenyl, 3

methyl-1-butenyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, 4

hexenyl, 5-hexenyl, 1-methyl-2-pentenyl, and 3-methyl-1

pentenyl. The alkenyl group may be a C2-C4 alkenyl group.

[0030] The "C2-C6 alkynyl group" means an alkynyl group

having 2 to 6 carbon atoms, and the alkynyl group may be

a linear alkynyl group or may be a branched alkynyl

group. Examples of the alkynyl group include ethynyl, 1

propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 3-butynyl, 1

methyl-2-propynyl, 1,1-dimethyl-2-propynyl, 1-pentynyl,

2-pentynyl, 3-pentynyl, 4-pentynyl, 1-methyl-2-butynyl,

3-methyl-1-butynyl, 1-hexynyl, 2-hexynyl, 3-hexynyl, 4

hexynyl, 5-hexynyl, 1-methyl-2-pentynyl, and 3-methyl-1

pentynyl. The alkynyl group may be a C2-C4 alkynyl group.

221102_G2572WO English Translation (Final) clean copy

[0031] The "C1-C6 alkoxy group" means a group in which the

"C1-C6 alkyl group" is bonded via an oxygen atom. The

alkoxy group may be a linear alkoxy group or may be a

branched alkoxy group. Examples of the alkoxy group

include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy,

isobutoxy, sec-butoxy, tert-butoxy, n-pentoxy,

isopentoxy, neopentoxy, tert-pentoxy, n-hexoxy,

isohexoxy, neohexoxy, and tert-hexoxy. The alkoxy group

may be a C1-C4 alkoxy group.

[0032] The "C1-C6 haloalkoxy group" means a group in which

at least one hydrogen of the "C1-C6 alkoxy group" is

replaced with a halogen atom. The haloalkoxy group may

be a linear haloalkoxy group or may be a branched

haloalkoxy group. Examples of the haloalkoxy group

include fluoromethoxy, chloromethoxy, bromomethoxy,

iodomethoxy, difluoromethoxy, dichloromethoxy,

dibromomethoxy, diiodomethoxy, trifluoromethoxy,

trichloromethoxy, tribromomethoxy, triiodomethoxy, 2

fluoroethoxy, 2-chloroethoxy, 2-bromoethoxy, 2

iodoethoxy, 2,2-difluoroethoxy, 2,2-dichloroethoxy, 2,2

dibromoethoxy, 2,2-diiodoethoxy, 2,2,2-trifluoroethoxy,

2,2,2-trichloroethoxy, 2,2,2-tribromoethoxy, 2,2,2

triiodoethoxy, 3-fluoropropoxy, 3-chloropropoxy, 3

bromopropoxy, 3-iodopropoxy, 4-fluorobutoxy, 4

chlorobutoxy, 4-bromobutoxy, 4-iodobutoxy, 5

fluoropentoxy, 5-chloropentoxy, 5-bromopentoxy, 5

iodopentoxy, 6-fluorohexoxy, 6-chlorohexoxy, 6

221102_G2572WO English Translation (Final) clean copy

bromohexoxy, and 6-iodohexoxy. The haloalkoxy group may

be a C1-C4 haloalkoxy group.

[0033] The "C3-C6 cycloalkyl group" means an alicyclic

saturated hydrocarbon group having 3 to 6 ring-forming

carbon atoms. Examples of the cycloalkyl group include

cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

[0034] The "C3-C6 cycloalkenyl group" means an alicyclic

unsaturated hydrocarbon group having 3 to 6 ring-forming

carbon atoms and having at least one carbon-carbon double

bond in the ring. Examples of the cycloalkenyl group

include cyclopropenyl, cyclobutenyl, cyclopentenyl, and

cyclohexenyl (2-cyclohexenyl and 3-cyclohexenyl).

[0035] The "C3-C6 cycloalkoxy group" means a group in

which the "C3-C6 cycloalkyl group" is bonded via an

oxygen atom. Examples of the cycloalkoxy group include

cyclopropoxy, cyclobutoxy, cyclopentoxy, and cyclohexoxy.

[0036] The "heterocyclyl group" means a saturated

monovalent heterocyclic group or a nonaromatic

unsaturated monovalent heterocyclic group containing at

least one heteroatom selected from a nitrogen atom, an

oxygen atom and a sulfur atom, and is preferably a

saturated monovalent heterocyclic group having 5 to 10

ring-forming atoms. Examples of the heterocyclyl group

include azetidinyl, oxetanyl, thietanyl, pyrrolidinyl,

piperidinyl, tetrahydrofuryl, tetrahydropyranyl,

tetrahydrothienyl (i.e., thiolanyl), piperazinyl, and

morpholinyl.

221102_G2572WO English Translation (Final) clean copy

[0037] The "C1-C6 alkoxycarbonyl group" means a group in

which the "C1-C6 alkoxy group" is bonded via a carbonyl

group. The alkoxycarbonyl group may be a linear

alkoxycarbonyl group or may be a branched alkoxycarbonyl

group. Examples of the alkoxycarbonyl group include

methoxycarbonyl, ethoxycarbonyl, n-propoxycarbonyl,

isopropoxycarbonyl, n-butoxycarbonyl, isobutoxycarbonyl,

sec-butoxycarbonyl, tert-butoxycarbonyl, n

pentoxycarbonyl, isopentoxycarbonyl, neopentoxycarbonyl,

tert-pentoxycarbonyl, n-hexoxycarbonyl,

isohexoxycarbonyl, neohexoxycarbonyl, and tert

hexoxycarbonyl. The alkoxycarbonyl group may be a C1-C4

alkoxycarbonyl group.

[0038] The "C1-C6 alkylsulfanyl group" means a group in

which the "C1-C6 alkyl group" is bonded via a sulfur

atom. The alkylsulfanyl group may be a linear

alkylsulfanyl group or may be a branched alkylsulfanyl

group. Examples of the alkylsulfanyl group include

methylsulfanyl, ethylsulfanyl, n-propylsulfanyl,

isopropylsulfanyl, n-butylsulfanyl, isobutylsulfanyl,

sec-butylsulfanyl, tert-butylsulfanyl, n-pentylsulfanyl,

isopentylsulfanyl, neopentylsulfanyl, tert

pentylsulfanyl, n-hexylsulfanyl, isohexylsulfanyl,

neohexylsulfanyl, and tert-hexylsulfanyl. The

alkylsulfanyl group may be a C1-C4 alkylsulfanyl group.

[0039] The "C1-C6 alkylsulfonyl group" means a group in

which the "C1-C6 alkyl group" is bonded via a sulfonyl

221102_G2572WO English Translation (Final) clean copy

group. The alkylsulfonyl group may be a linear

alkylsulfonyl group or may be a branched alkylsulfonyl

group. Examples of the alkylsulfonyl group include

methylsulfonyl, ethylsulfonyl, n-propylsulfonyl,

isopropylsulfonyl, n-butylsulfonyl, isobutylsulfonyl,

sec-butylsulfonyl, tert-butylsulfonyl, n-pentylsulfonyl,

isopentylsulfonyl, neopentylsulfonyl, tert

pentylsulfonyl, n-hexylsulfonyl, isohexylsulfonyl,

neohexylsulfonyl, and tert-hexylsulfonyl. The

alkylsulfonyl group may be a C1-C4 alkylsulfonyl group.

[0040] In the present specification, the

"pharmaceutically acceptable salt" includes a

pharmaceutically acceptable acid-addition salt and a salt

with a pharmaceutically acceptable acid (hereinafter,

these are also collectively referred to as an "acid

addition salt, etc."), and a pharmaceutically acceptable

base-addition salt and a salt with a pharmaceutically

acceptable base (hereinafter, these are also collectively

referred to as a "base-addition salt, etc.").

[0041] In the present specification, examples of the

"acid-addition salt" or the "salt with an acid" (acid

addition salt, etc.) include hydrochloride, hydrobromide,

sulfate, nitrate, phosphate, acetate, oxalate, malonate,

fumarate, maleate, phthalate, trifluoroacetate,

methanesulfonate, benzenesulfonate, p-toluenesulfonate,

2,4-dimethylbenzenesulfonate, 2,4,6

221102_G2572WO English Translation (Final) clean copy

trimethylbenzenesulfonate, 4-ethylbenzenesulfonate, and

naphthalenesulfonate.

[0042] In the present specification, the "base-addition

salt" or the "salt with a base" (base-addition salt,

etc.) includes, for example, a metal salt, an inorganic

amine salt, an organic amine salt, and an amino acid

salt. The metal salt may be, for example, an alkali

metal salt such as sodium salt, potassium salt, or

lithium salt; an alkaline earth metal salt such as

calcium salt or magnesium salt; aluminum salt; iron salt;

zinc salt; copper salt; nickel salt; or cobalt salt. The

inorganic amine salt may be, for example, ammonium salt.

The organic amine salt may be, for example, morpholine

salt, glucosamine salt, ethylenediamine salt, guanidine

salt, diethylamine salt, triethylamine salt,

dicyclohexylamine salt, diethanolamine salt, piperazine

salt, or tetramethylammonium salt. Examples of the amino

acid salt include glycine salt, lysine salt, arginine

salt, ornithine salt, glutamate, and aspartate.

[0043] In the present specification, the "disease related

to integrin av" is a disease involving integrin axv and

is not particularly limited as long as its symptom is

alleviated, improved, suppressed, or prevented by

inhibiting integrin av. Integrins are heterodimers

composed of a and $ chains. The integrin av is an a

chain. Integrins comprising integrin av include

integrins axvpl, axvP3, axvP5, axvf6 and av8. The "disease

221102_G2572WO English Translation (Final) clean copy

related to integrin av" may include a disease related to

integrin avvpl, axvP3, axvP5, axvf6 or av8 because these

integrins comprise integrin av. The "disease related to

integrin av" includes, for example, a "disease related to

integrin av$l" or a "disease related to integrin av$6".

Examples of the disease related to integrin av

include inflammatory disease, fibrosis, cancer,

neurodegenerative disease, eye disease, osteoporosis, and

osteogenesis imperfecta. The inhibition of integrin av

includes decrease in the degree of signals mediated by

integrin av, as compared with a control, or decrease in

the ability of integrin av to bind to a ligand, as

compared with a control.

[0044] In the present specification, the "inflammatory

disease" refers to a disease, disorder, or a condition

related to inflammation. Examples thereof include, but

are not limited to, arthritis, rheumatoid arthritis,

Crohn disease, irritable bowel disease, inflammatory

bowel disease(IBD), systemic erythematosus, gum disease,

psoriasis, acute hepatitis, chronic hepatitis, Alport's

syndrome, inflammation caused by diabetes mellitus, joint

arterial inflammation, large-cell arterial inflammation,

Kawasaki disease, Takayasu arteritis, Churg-Strauss

syndrome and Henoch-Schonlein purpura.

[0045] In the present specification, examples of the

"fibrosis" include, but are not particularly limited to,

fibroses in the lung, the liver, the kidney, the heart,

221102_G2572W English Translation (Final) clean copy

vascular vessels, the skin, the pancreas, the bone

marrow, and other organs or tissues. In the present

invention, the fibrosis is preferably pulmonary fibrosis,

hepatic fibrosis, renal fibrosis, cardiac fibrosis,

vascular fibrosis, dermatofibrosis, pancreatic fibrosis,

myelofibrosis or skeletal myofibrosis, more preferably

pulmonary fibrosis, hepatic fibrosis, renal fibrosis or

cardiac fibrosis.

The pulmonary fibrosis includes idiopathic pulmonary

fibrosis (IPF), non-specific interstitial pneumonia

(NSIP), cryptogenic organizing pneumonia (COP), acute

interstitial pneumonia (AIP), interstitial lung disease,

peribronchiolar fibrosis, peripheral airway disease

(e.g., bronchiolitis obliterans), pulmonary emphysema,

acute respiratory distress syndrome (ARDS), acute lung

injury (ALI), postinfectious pulmonary fibrosis, drug

induced pulmonary fibrosis, airway fibrosis, diffuse

alveolar damage, collagen-vascular disease-related

pulmonary fibrosis, silicosis, radiation-induced

fibrosis, bleomycin-induced fibrosis, influenza-induced

fibrosis, asbestos-induced pulmonary fibrosis,

desquamative interstitial pneumonia and chronic

hypersensitivity pneumonitis.

The hepatic fibrosis includes primary biliary

cholangitis (PBC), primary sclerosing cholangitis (PSC),

infectious hepatic fibrosis (caused by HCV or a parasite

such as blood fluke), alcoholic steatohepatitis (ASH),

221102_G2572WO English Translation (Final) clean copy

non-alcoholic fatty liver disease (NAFLD), non-alcoholic

steatohepatitis (NASH), liver cirrhosis caused by every

etiology, congenital hepatic fibrosis, Sjogren's

syndrome, sarcoidosis, Wilson's disease, Gaucher's

disease, hemochromatosis, and al-antitrypsin deficiency.

The renal fibrosis includes chronic kidney disease

(CKD), glomerulonephritis (GN) of every etiology,

mesangial proliferative GN, immune GN, crescentic GN,

tubulointerstitial injury, renal interstitial fibrosis,

renal fibrosis brought about by complications of drug

exposure (including the cyclosporine treatment of

transplantation recipients), nephrogenic systemic

fibrosis, HIV-related nephropathy, graft nephropathy,

diabetic kidney disease (diabetic nephropathy), focal

segmental glomerulosclerosis (FSGS), idiopathic

retroperitoneal fibrosis, hypertensive nephrosclerosis

and IgA nephropathy.

The cardiac fibrosis and the vascular fibrosis

include cardiac fibrosis associated with myocardial

infarction, vascular injury-induced fibrosis, cardiac

stenosis, aortostenosis, atherosclerosis, thrombosis,

arteriosclerosis, myocardial infarction, angina pectoris,

cardiac valvular disease, renal arteriosclerosis,

congestive heart failure, dilated cardiomyopathy,

hypertrophic cardiomyopathy, restrictive cardiomyopathy,

myocarditis, vascular stenosis cardiac fibrosis, post

infarction cardiac fibrosis, left ventricular

221102_G2572WO English Translation (Final) clean copy

hypertrophy, venous occlusion, restenosis, restenosis

after angiogenesis, arteriovenous transplantation

failure, hypertension, hypertensive heart disease,

cardiomegaly, heart failure, aortic disease, hereditary

hemorrhagic telangiectasia (HHT), arterial tortuosity

syndrome, Raynaud syndrome and hypertriglyceridemia.

The dermatofibrosis includes generalized

scleroderma, polymyositis, systemic lupus erythematosus,

dermatomyositis, Dupuytren's contracture, postoperative

adhesion, fibrosis caused by surgical incision or

mechanical trauma, and excessive or hypertrophic scarring

or keloid formation in the dermis during wound healing

brought about from trauma or surgical wound.

The pancreatic fibrosis includes cystic fibrosis

(CF), chronic pancreatitis, and autoimmune pancreatitis.

The myelofibrosis includes primary myelofibrosis,

idiopathic myelofibrosis, secondary myelofibrosis, and

myeloproliferative tumor.

The fibrosis in other organs or tissues includes

skeletal myofibrosis, intestinal fibrosis, fibrosis after

organ transplantation, induratio penis plastica (Peyronie

disease), bladder fibrosis, Camurati-Engelmann disease,

Loeys-Dietz syndrome, Marfan syndrome, premature ovarian

failure, preeclampsia, mediastinal fibrosis, and

intestinal stenosis.

[0046] In the present specification, the "cancer"

includes tumor angiogenesis, carcinoma, sarcoma,

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lymphoma, leukemia, melanoma, mesothelioma, multiple

myeloma, seminoma, and tumor metastasis. Examples of the

tumor site that may be treated according to the present

invention include the bladder, blood, bone, the brain,

the breast, the central nervous system, the uterine

cervix, the colon, the endometrium, the esophagus, the

gallbladder, the genital organ, the genitourinary tract,

the head, the kidney, the larynx, the liver, the lung,

muscular tissues, the neck, oral or nasal mucosa, the

ovary, the pancreas, the prostate, the skin, the spleen,

the small intestine, the large intestine, the stomach,

the testis, and the thyroid gland.

[0047] In the present specification, the

"neurodegenerative disease" includes peripheral nerve

disorder, Alzheimer's disease, Parkinson's disease, and

multiple sclerosis.

[0048] In the present specification, the "eye disease"

includes age-related macular degeneration (AMD),

glaucoma, ocular fibrosis, retinal or corneal scarring,

diabetic retinopathy, proliferative vitreoretinopathy

(PVR), vitreoretinopathy of arbitrary etiology, fibrosis

related to ophthalmic surgery, retinal reattachment

surgery, cataract extraction, or an arbitrary type of

drainage treatment, scarring in the cornea and the

conjunctiva, corneal endothelial fibrosis, alkaline burn

(e.g., alkaline burn in the cornea), capsulolenticular

fibrosis after cataract operation, excessive scarring in

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tissues surrounding extraocular muscle in strabismus

operation, anterior subcapsular cataract and posterior

capsule opacification, anterior eye fibrosis, corneal

stromal fibrosis, fibrosis related to corneal clouding,

trabecular meshwork fibrosis, fibrosis related to

glaucoma, posterior eye fibrosis, fibrovascular scarring,

fibrosis in the retinal blood vessel or choroid blood

vessel of the eye, retinal fibrosis, epiretinal fibrosis,

retinal gliosis, subretinal fibrosis, fibrosis related to

retinal operation and glaucoma operation, retinal

traction detachment related to tissue contraction in

diabetic retinopathy, scarring of cicatricial pemphigoid

glaucoma filtration surgery, retinopathy of prematurity

(ROP) and familial exudative vitreoretinopathy (FEVR).

[0049] In the present specification, the "subject" is a

human, a monkey, a bovine, a horse, sheep, a goat, a

rabbit, a dog, a cat, a mouse, a rat, a guinea pig or a

transgenic species thereof. In the present

specification, the subject is an individual in need of

the treatment of the disease.

[0050] In the present specification, the "treatment"

includes at least one of prevention, alleviation and

remedy and also encompasses reduction of a symptom of the

disease, suppression of the progression of a symptom of

the disease, removal of a symptom of the disease,

improvement in the prognosis of the disease, prevention

of the recurrence of the disease, and prevention of the

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disease. In one aspect of the present invention, the

treatment is remedy.

[0051] <Compound of present invention>

In one embodiment, the present invention relates to

a compound represented by the following general formula

(I) or (II) or a pharmaceutically acceptable salt

thereof:

Y Y

HN N O HN N O HN N N COR HN N CO2 R 0/ OA 0O A R 1x/ R N-NH HN-N

(I) (II) wherein

A is a C6-C10 aryl group or a heteroaryl group,

wherein at least one hydrogen atom of the aryl group or

the heteroaryl group is optionally replaced with a

substituent selected from the group consisting of a

halogen atom, a hydroxy group, a C1-C6 alkyl group, a C1

C6 haloalkyl group, a C2-C6 alkenyl group, a C2-C6 alkynyl

group, a C1-C6 alkoxy group, a C1-C6 haloalkoxy group, a

C3-C6 cycloalkyl group, a C3-C6 cycloalkenyl group, a C3-C6

cycloalkoxy group, a heterocyclyl group, a heteroaryl

group optionally substituted by a C1-C6 alkyl group, a

cyano group, a carboxyl group, a carbamoyl group, a C1-C6

alkoxycarbonyl group, a C1-C6 alkylsulfanyl group, and a

C1-C6 alkylsulfonyl group,

221102_G2572WO English Translation (Final) clean copy

R is a hydrogen atom or a C1-C6 alkyl group,

R' is a hydrogen atom or a halogen atom, and

Y is a hydrogen atom, a fluorine atom or a hydroxy

group.

In the present specification, the compound

represented by the general formula (I) is also simply

referred to as a "compound (I)" and the compound

represented by the general formula (II) is also simply

referred to as a "compound (II)".

[0052] In one embodiment of the present invention, A in

the compound (I) or (II) is preferably a phenyl group.

At least one hydrogen atom of the phenyl group that

may be selected as A is optionally replaced with a

substituent selected from the group consisting of a

halogen atom, a hydroxy group, a C1-C6 alkyl group, a C1

C6 haloalkyl group, a C2-C6 alkenyl group, a C2-C6 alkynyl

group, a C1-C6 alkoxy group, a C1-C6 haloalkoxy group, a

C3-Cs6 cycloalkyl group, a C3-Cs6 cycloalkenyl group, a C3-Cs6

cycloalkoxy group, a heterocyclyl group, a heteroaryl

group optionally substituted by a C1-C6 alkyl group, a

cyano group, a carboxyl group, a carbamoyl group, a C1-C6

alkoxycarbonyl group, a C1-C6 alkylsulfanyl group, and a

C1-C6 alkylsulfonyl group.

[0053] At least one hydrogen atom of the phenyl group

that may be selected as A is optionally replaced with a

substituent selected from the group consisting of a

halogen atom, a hydroxy group, a C1-C6 alkyl group, a C1

221102_G2572WO English Translation (Final) clean copy

C6 haloalkyl group, a C2-C6 alkenyl group, a C1-C alkoxy

group, a C1-C6 haloalkoxy group, a C3-C6 cycloalkyl group,

a C3-C6 cycloalkenyl group, a C3-C6 cycloalkoxy group, a

heterocyclyl group, a heteroaryl group optionally

substituted by a C1-C alkyl group, a cyano group, a

carboxyl group, a carbamoyl group, a C1-C6 alkoxycarbonyl

group, a C1-C6 alkylsulfanyl group, and a C1-C6

alkylsulfonyl group.

[0054] In another embodiment of the present invention, at

least one hydrogen atom of the phenyl group that may be

selected as A is optionally replaced with a substituent

selected from the group consisting of a halogen atom, a

C1-C6 alkyl group, a C1-C6 haloalkyl group, a C1-C6 alkoxy

group, a C1-C6 haloalkoxy group, a C3-C6 cycloalkyl group,

a C3-C6 cycloalkoxy group, a heterocyclyl group, and a

heteroaryl group optionally substituted by a C1-C6 alkyl

group.

[0055] In an alternative embodiment of the present

invention, A in the compound (I) or (II) may be a group

represented by the following formula (i):

R6 R2

R5 RRR3

0)

[0056] In the formula (i), R 2 is a hydrogen atom or a

halogen atom.

221102_G2572WO English Translation (Final) clean copy

In another embodiment, R 2 is a hydrogen atom, a

fluorine atom or a chlorine atom.

In an alternative embodiment, R 2 is a hydrogen atom.

[0057] R3 is a hydrogen atom, a halogen atom, a C1-C6

alkyl group, a C1-C6 haloalkyl group, a C1-C6 alkoxy

group, a C1-C6 haloalkoxy group, a C3-Cs6 cycloalkyl group,

a C3-C6 cycloalkoxy group, a heterocyclyl group, or a

heteroaryl group optionally substituted by a C1-C6 alkyl

group.

In another embodiment, R 3 is a hydrogen atom, a

halogen atom, a C1-C6 haloalkyl group, a C1-C6 haloalkoxy

group, a C3-C6 cycloalkyl group, a C3-C6 cycloalkoxy

group, a heterocyclyl group, or a heteroaryl group

optionally substituted by a C1-C4 alkyl group.

In an alternative embodiment, R 3 is a hydrogen atom,

a halogen atom, a C1-C4 haloalkyl group, a C1-C4

haloalkoxy group, a C3-C6 cycloalkyl group, a C3-C6

cycloalkoxy group, a heterocyclyl group, or a heteroaryl

group.

In an alternative embodiment, R 3 is a hydrogen atom,

a halogen atom, a difluoromethyl group, a trifluoromethyl

group, a difluoromethoxy group, a trifluoromethoxy group,

a cyclopropyl group, a cyclopropoxy group, a morpholinyl

group, or a pyrazolinyl group.

In an alternative embodiment, R 3 is a hydrogen atom,

a halogen atom, a C1-C6 alkyl group, a C1-C6 haloalkyl

group, a C1-C6 alkoxy group, a C1-C6 haloalkoxy group, or

221102_G2572WO English Translation (Final) clean copy

a heteroaryl group optionally substituted by a C1-C6

alkyl group.

In an alternative embodiment, R 3 is a hydrogen atom,

a halogen atom, a C1-C4 alkyl group, a C1-C4 haloalkyl

group, a C1-C4 alkoxy group, a C1-C4 haloalkoxy group, or

a heteroaryl group optionally substituted by a C1-C4

alkyl group.

In an alternative embodiment, R 3 is a halogen atom,

a methyl group, a difluoromethyl group, a trifluoromethyl

group, a methoxy group, a difluoromethoxy group, a

trifluoromethoxy group, or a pyrazolinyl group optionally

substituted by a methyl group.

In an alternative embodiment, R 3 is a halogen atom,

a trifluoromethyl group, a difluoromethoxy group, a

trifluoromethoxy group, or a pyrazolinyl group.

[0058] R4 is a hydrogen atom, a halogen atom, a C1-C6

alkyl group, a C1-C6 haloalkyl group, a C1-C6 alkoxy

group, or a C1-C6 haloalkoxy group.

In another embodiment, R 4 is a hydrogen atom, a

halogen atom, a C1-C4 alkyl group, a C1-C4 haloalkyl

group, a C1-C4 alkoxy group, or a C1-C4 haloalkoxy group.

In an alternative embodiment, R 4 is a hydrogen atom,

a halogen atom, a methyl group, a trifluoromethyl group,

a methoxy group, or a difluoromethoxy group.

In an alternative embodiment, R 4 is a hydrogen atom

or a halogen atom.

221102_G2572WO English Translation (Final) clean copy

In an alternative embodiment, R 4 is a hydrogen atom

or a fluorine atom.

[0059] R5 is a hydrogen atom, a halogen atom, a C1-C6

alkyl group, a C1-C6 haloalkyl group, a C1-C6 alkoxy

group, a C1-C6 haloalkoxy group, or a heteroaryl group

optionally substituted by a C1-C6 alkyl group.

In another embodiment, R 5 is a hydrogen atom, a

halogen atom, a C1-C4 alkyl group, a C1-C4 haloalkyl

group, a C1-C4 alkoxy group, a C1-C4 haloalkoxy group, or

a pyrazolinyl group.

In an alternative embodiment, R5 is a hydrogen atom,

a halogen atom, a methyl group, a trifluoromethyl group,

a methoxy group, a difluoromethoxy group, or a

pyrazolinyl group.

In an alternative embodiment, R5 is a hydrogen atom,

a halogen atom, a C1-C6 alkyl group, a C1-C6 haloalkyl

group, a C1-C6 alkoxy group, or a C1-C6 haloalkoxy group.

In an alternative embodiment, R5 is a hydrogen atom,

a halogen atom, a C1-C4 alkyl group, a C1-C4 haloalkyl

group, a C1-C4 alkoxy group, or a C1-C4 haloalkoxy group.

In an alternative embodiment, R5 is a hydrogen atom,

a halogen atom, a methyl group, a difluoromethyl group, a

trifluoromethyl group, a methoxy group, a difluoromethoxy

group, or a trifluoromethoxy group.

In an alternative embodiment, R5 is a halogen atom,

a methyl group, a trifluoromethyl group, a

difluoromethoxy group, or a trifluoromethoxy group.

221102_G2572WO English Translation (Final) clean copy

[0060] R6 is a hydrogen atom or a halogen atom.

In another embodiment, R 6 is a hydrogen atom, a

fluorine atom or a chlorine atom.

In an alternative embodiment, R 6 is a hydrogen atom

or a fluorine atom.

[0061] In an alternative embodiment, for example, in the

formula (i),

R 2 may be a hydrogen atom,

R 3 may be a hydrogen atom, a halogen atom, a C1-C6

alkyl group, a C1-C6 haloalkyl group, a C1-C6 alkoxy

group, a C1-C6 haloalkoxy group, or a heteroaryl group

optionally substituted by a C1-C6 alkyl group,

R 4 may be a hydrogen atom or a halogen atom,

R5 may be a hydrogen atom, a halogen atom, a C1-C6

alkyl group, a C1-C6 haloalkyl group, a C1-C6 alkoxy

group, or a C1-C6 haloalkoxy group, and

R 6 may be a hydrogen atom or a halogen atom.

[0062] In an alternative embodiment, in the formula (i),

R 2 may be a hydrogen atom,

R 3 may be a hydrogen atom, a halogen atom, a C1-C6

haloalkyl group, a C1-C6 haloalkoxy group, a C3-C6

cycloalkyl group, a C3-C6 cycloalkoxy group, a

heterocyclyl group, or a heteroaryl group optionally

substituted by a C1-C4 alkyl group,

R 4 may be a hydrogen atom or a halogen atom,

221102_G2572WO English Translation (Final) clean copy

R 5 may be a hydrogen atom, a halogen atom, a C1-C6

alkyl group, a C1-C6 haloalkyl group, a C1-C6 alkoxy

group, or a C1-C6 haloalkoxy group, and

R 6 may be a hydrogen atom or a halogen atom.

[0063] In an alternative embodiment of the present

invention, A in the compound (I) or (II) may be a group

represented by any of the following formulas (i)-a to

(i)-g:

RaR R~ 6 12 Ral Ra2 R a Ra R'311 Ra Ra Ralo R

(i)-a (i)-b (i)-c (i)-d (i)-e (i)-f (i-g

wherein * represents a binding position, and Rai to Ra13 are each independently a substituent

selected from the group consisting of a halogen atom, a

hydroxy group, a C1-C6 alkyl group, a C1-C6 haloalkyl

group, a C2-C6 alkenyl group, a C2-C6 alkynyl group, a C1

C6 alkoxy group, a C1-C6 haloalkoxy group, a C3-C6

cycloalkyl group, a C3-C6 cycloalkenyl group, a C3-C6

cycloalkoxy group, a heterocyclyl group, a heteroaryl

group optionally substituted by a C1-C6 alkyl group, a

cyano group, a carboxyl group, a carbamoyl group, a C1-C6

alkoxycarbonyl group, a C1-C6 alkylsulfanyl group, and a

C1-C6 alkylsulfonyl group. Rai

[0064] In the embodiment, to Ra 1 3 may each

independently be a substituent selected from the group

consisting of a halogen atom, a C1-C6 alkyl group, a C1-C6

221102_G2572WO English Translation (Final) clean copy

haloalkyl group, a C1-C6 alkoxy group, a C1-C6 haloalkoxy

group, a C3-C6 cycloalkyl group, a C3-C6 cycloalkoxy

group, a heterocyclyl group, and a heteroaryl group

optionally substituted by a C1-C6 alkyl group.

[0065] In an alternative embodiment of the present

invention, when A in the compound (I) or (II) is a group

represented by the formula (i)-a,

one of Rai and Ra 2 may be a halogen atom, a C1-C6

haloalkyl group, or a C1-C6 haloalkoxy group, and

the other moiety may be a halogen atom, a C1-C6 alkyl

group, a C1-C6 haloalkyl group, a C1-C6 alkoxy group, a

C1-C6 haloalkoxy group, a C3-C6 cycloalkyl group, a C3-C6

cycloalkoxy group, a heterocyclyl group, or a heteroaryl

group optionally substituted by a C1-C6 alkyl group.

[0066] In an alternative embodiment of the present

invention, when A in the compound (I) or (II) is a group

represented by the formula (i)-a, Rai one of and Ra 2 may be a halogen atom, a

trifluoromethyl group, a difluoromethoxy group, or a

trifluoromethoxy group, and

the other moiety may be a halogen atom, a C1-C6 alkyl

group, a C1-C6 haloalkyl group, a C1-C6 alkoxy group, a

C1-C6 haloalkoxy group, a C3-C6 cycloalkyl group, a C3-C6

cycloalkoxy group, a heterocyclyl group, or a heteroaryl

group optionally substituted by a C1-C6 alkyl group.

221102_G2572WO English Translation (Final) clean copy

[0067] In an alternative embodiment of the present

invention, when A in the compound (I) or (II) is a group

represented by the formula (i)-a,

one of Rai and Ra 2 may be a halogen atom, a

difluoromethyl group, a trifluoromethyl group, a

difluoromethoxy group, or a trifluoromethoxy group, and

the other moiety may be a halogen atom, a methyl

group, a difluoromethyl group, a trifluoromethyl group, a

methoxy group, a difluoromethoxy group, a

trifluoromethoxy group, a cyclopropyl group, a

cyclopropoxy group, a morpholinyl group, or a pyrazolinyl

group.

[0068] In an alternative embodiment of the present

invention, when A in the compound (I) or (II) is a group

represented by the formula (i)-b,

Ra3 may be a halogen atom, and

Ra 4 may be a halogen atom, a C1-C6 alkyl group, a C1

C6 haloalkyl group, a C1-C6 alkoxy group, a C1-C6

haloalkoxy group, a C3-C6 cycloalkyl group, a C3-C6

cycloalkoxy group, a heterocyclyl group, or a heteroaryl

group optionally substituted by a C1-C6 alkyl group.

[0069] In an alternative embodiment of the present

invention, when A in the compound (I) or (II) is a group

represented by the formula (i)-b,

Ra3 may be a halogen atom, and

Ra 4 may be a halogen atom, a C1-C6 haloalkyl group,

or a C1-C6 haloalkoxy group.

221102_G2572WO English Translation (Final) clean copy

[0070] In an alternative embodiment of the present

invention, when A in the compound (I) or (II) is a group

represented by the formula (i)-b,

Ra3 may be a halogen atom, and

Ra 4 may be a C1-C6 haloalkyl group.

[0071] In an alternative embodiment of the present

invention, when A in the compound (I) or (II) is a group

represented by the formula (i)-c,

Ra5 may be a halogen atom, and

Ra6 may be a halogen atom, a C1-C6 alkyl group, a C1

C6 haloalkyl group, a C1-C6 alkoxy group, a C1-C6

haloalkoxy group, a C3-C6 cycloalkyl group, a C3-C6

cycloalkoxy group, a heterocyclyl group, or a heteroaryl

group optionally substituted by a C1-C6 alkyl group.

[0072] In an alternative embodiment of the present

invention, when A in the compound (I) or (II) is a group

represented by the formula (i)-c,

Ra5 may be a halogen atom, and

Ra6 may be a halogen atom, a C1-C6 haloalkyl group,

or a C1-C6 haloalkoxy group.

[0073] In an alternative embodiment of the present

invention, when A in the compound (I) or (II) is a group

represented by the formula (i)-c,

Ra5 may be a halogen atom, and

Ra6 may be a halogen atom, a trifluoromethyl group,

or a trifluoromethoxy group.

221102_G2572WO English Translation (Final) clean copy

[0074] In an alternative embodiment of the present

invention, when A in the compound (I) or (II) is a group

represented by the formula (i)-d,

one of Ra7 and Ra8 may be a halogen atom, a C1-C6

haloalkyl group, or a C1-C6 haloalkoxy group, and

the other moiety may be a halogen atom, a C1-C6 alkyl

group, a C1-C6 haloalkyl group, a C1-C6 alkoxy group, a

C1-C haloalkoxy group, a C3-C6 cycloalkyl group, a C3-C6

cycloalkoxy group, a heterocyclyl group, or a heteroaryl

group optionally substituted by a C1-C6 alkyl group.

[0075] In an alternative embodiment of the present

invention, when A in the compound (I) or (II) is a group

represented by the formula (i)-d,

one of Ra7 and Ra8 may be a halogen atom, a C1-C6

haloalkyl group, or a C1-C6 haloalkoxy group, and

the other moiety may be a halogen atom, a C1-C6 alkyl

group, a C1-C6 haloalkyl group, a C1-C6 alkoxy group, or a

C1-C6 haloalkoxy group.

[0076] In an alternative embodiment of the present

invention, when A in the compound (I) or (II) is a group

represented by the formula (i)-d,

one of Ra7 and Ra8 may be a halogen atom, a

trifluoromethyl group, or a trifluoromethoxy group, and

the other moiety may be a halogen atom, a methyl

group, a difluoromethyl group, a trifluoromethyl group, a

methoxy group, a difluoromethoxy group, or a

trifluoromethoxy group.

221102_G2572WO English Translation (Final) clean copy

[0077] In an alternative embodiment of the present

invention, when A in the compound (I) or (II) is a group

represented by the formula (i)-e, Raio at least one of Rag, and Ral may be a halogen

atom, a C1-C6 haloalkyl group, or a C1-C6 haloalkoxy

group, and

the remaining moieties may each individually be a

halogen atom, a C1-C6 alkyl group, a C1-C6 haloalkyl

group, a C1-C6 alkoxy group, a C1-C6 haloalkoxy group, a

C3-C6 cycloalkyl group, a C3-C6 cycloalkoxy group, a

heterocyclyl group, or a heteroaryl group optionally

substituted by a C1-C6 alkyl group.

[0078] In an alternative embodiment of the present

invention, when A in the compound (I) or (II) is a group

represented by the formula (i)-e, Raio Ra9, and Ra1 1 may each individually be a halogen

atom, a C1-C6 haloalkyl group, or a C1-C6 haloalkoxy

group.

[0079] In an alternative embodiment of the present

invention, when A in the compound (I) or (II) is a group

represented by the formula (i)-f,

Ra 1 2 may be a halogen atom, a C1-C6 haloalkyl group, a

C1-C6 haloalkoxy group, a C3-C6 cycloalkyl group, a C3-C6

cycloalkoxy group, a heterocyclyl group, or a heteroaryl

group optionally substituted by a C1-C6 alkyl group.

221102_G2572WO English Translation (Final) clean copy

[0080] In an alternative embodiment of the present

invention, when A in the compound (I) or (II) is a group

represented by the formula (i)-f,

Ra1 2 may be a halogen atom, a difluoromethyl group, a

trifluoromethyl group, a difluoromethoxy group, a

trifluoromethoxy group, a cyclopropyl group, a

cyclopropoxy group, a morpholinyl group, or a pyrazolinyl

group optionally substituted by a methyl group.

[0081] In an alternative embodiment of the present

invention, when A in the compound (I) or (II) is a group

represented by the formula (i)-g,

Ra1 3 may be a halogen atom, a C1-C6 haloalkyl group, a

C1-C6 haloalkoxy group, a C3-C6 cycloalkyl group, a C3-C6

cycloalkoxy group, a heterocyclyl group, or a heteroaryl

group optionally substituted by a C1-C6 alkyl group.

[0082] In an alternative embodiment of the present

invention, when A in the compound (I) or (II) is a group

represented by the formula (i)-f,

Rai 3 may be a halogen atom, a difluoromethyl group, a

trifluoromethyl group, a difluoromethoxy group, a

trifluoromethoxy group, a cyclopropyl group, a

cyclopropoxy group, a morpholinyl group, or a pyrazolinyl

group optionally substituted by a methyl group.

[0083] In an alternative embodiment of the present

invention, when A in the compound (I) or (II) is a group

represented by the formula (i)-f,

221102_G2572WO English Translation (Final) clean copy

Rai3 may be a C1-C6 haloalkyl group or a C1-C6

haloalkoxy group.

Alternatively, Rais may be a difluoromethyl group, a

trifluoromethyl group, a difluoromethoxy group, or a

trifluoromethoxy group.

[0084] In one embodiment, R in the compound (I) or (II)

is a hydrogen atom or a C1-C alkyl group.

In another embodiment, R in the compound (I) or (II)

is a hydrogen atom or a C1-C4 alkyl group.

In an alternative embodiment, R in the compound (I)

or (II) is a hydrogen atom or a methyl group.

In an alternative embodiment, R in the compound (I)

or (II) is a hydrogen atom.

[0085] In one embodiment, R' in the compound (I) or (II)

is a hydrogen atom or a halogen atom.

In another embodiment, R' in the compound (I) or

(II) is a hydrogen atom, a fluorine atom or a chlorine

atom.

In an alternative embodiment, R' in the compound (I)

or (II) is a hydrogen atom.

[0086] In one embodiment, Y in the compound (I) or (II)

is a hydrogen atom, a fluorine atom or a hydroxy group.

In an alternative embodiment, Y in the compound (I)

or (II) is a fluorine atom.

[0087] In an alternative embodiment, the present

invention provides a compound selected from the following

group or a pharmaceutically acceptable salt thereof:

221102_G2572WO English Translation (Final) clean copy

(3S)-3-(3-chloro-5-(trifluoromethyl)phenyl)-3-(2-(4

((5-fluoro-1,4,5,6-tetrahydropyrimidin-2-yl)amino)-1H

indazole-6-carboxamido)acetamido)propanoic acid,

(3S)-3-(3-bromo-5-(trifluoromethyl)phenyl)-3-(2-(4

((5-fluoro-1,4,5,6-tetrahydropyrimidin-2-yl)amino)-1H

indazole-6-carboxamido)acetamido)propanoic acid

(3S)-3-(2-(4-((5-fluoro-1,4,5,6-tetrahydropyrimidin

2-yl)amino)-1H-indazole-6-carboxamido)acetamido)-3-(3

iodo-5-(trifluoromethyl)phenyl)propanoic acid,

(3S)-3-(2-(4-((5-fluoro-1,4,5,6-tetrahydropyrimidin

2-yl)amino)-1H-indazole-6-carboxamido)acetamido)-3-(3

methyl-5-(trifluoromethyl)phenyl)propanoic acid,

(3S)-3-(2-(4-((5-fluoro-1,4,5,6-tetrahydropyrimidin

2-yl)amino)-1H-indazole-6-carboxamido)acetamido)-3-(3

methoxy-5-(trifluoromethyl)phenyl)propanoic acid,

(3S)-3-(2-(4-((5-fluoro-1,4,5,6-tetrahydropyrimidin

2-yl)amino)-1H-indazole-6-carboxamido)acetamido)-3-(3

fluoro-5-(trifluoromethyl)phenyl)propanoic acid,

(3S)-3-(3,5-bis(trifluoromethyl)phenyl)-3-(2-(4-((5

fluoro-1,4,5,6-tetrahydropyrimidin-2-yl)amino)-1H

indazole-6-carboxamido)acetamido)propanoic acid,

(3S)-3-(3-(1H-pyrazol-1-yl)-5

(trifluoromethyl)phenyl)-3-(2-(4-((5-fluoro-1,4,5,6

tetrahydropyrimidin-2-yl)amino)-1H-indazole-6

carboxamido)acetamido)propanoic acid,

221102_G2572WO English Translation (Final) clean copy

(3S)-3-(2-(4-((5-fluoro-1,4,5,6-tetrahydropyrimidin

2-yl)amino)-1H-indazole-6-carboxamido)acetamido)-3-(2

fluoro-3-(trifluoromethyl)phenyl)propanoic acid,

(3S)-3-(2-chloro-3-(trifluoromethyl)phenyl)-3-(2-(4

((5-fluoro-1,4,5,6-tetrahydropyrimidin-2-yl)amino)-1H

indazole-6-carboxamido)acetamido)propanoic acid,

(3S)-3-(2-(4-((5-fluoro-1,4,5,6-tetrahydropyrimidin

2-yl)amino)-1H-indazole-6-carboxamido)acetamido)-3-(2

fluoro-5-(trifluoromethyl)phenyl)propanoic acid,

(3S)-3-(2-chloro-5-(trifluoromethyl)phenyl)-3-(2-(4

((5-fluoro-1,4,5,6-tetrahydropyrimidin-2-yl)amino)-1H

indazole-6-carboxamido)acetamido)propanoic acid,

(3S)-3-(2-(4-((5-fluoro-1,4,5,6-tetrahydropyrimidin

2-yl)amino)-1H-indazole-6-carboxamido)acetamido)-3-(4

fluoro-3-(trifluoromethyl)phenyl)propanoic acid,

(3S)-3-(2-(4-((5-fluoro-1,4,5,6-tetrahydropyrimidin

2-yl)amino)-1H-indazole-6-carboxamido)acetamido)-3-(4

methyl-3-(trifluoromethyl)phenyl)propanoic acid,

(3S)-3-(3-chloro-4-fluoro-5

(trifluoromethyl)phenyl)-3-(2-(4-((5-fluoro-1,4,5,6

tetrahydropyrimidin-2-yl)amino)-1H-indazole-6

carboxamido)acetamido)propanoic acid,

(3S)-3-(3-bromo-4-methoxyphenyl)-3-(2-(4-((5-fluoro

1,4,5,6-tetrahydropyrimidin-2-yl)amino)-1H-indazole-6

carboxamido)acetamido)propanoic acid,

221102_G2572WO English Translation (Final) clean copy

(3S)-3-(3,5-dichlorophenyl)-3-(2-(4-((5-fluoro

1,4,5,6-tetrahydropyrimidin-2-yl)amino)-1H-indazole-6

carboxamido)acetamido)propanoic acid,

(3S)-3-(3-bromo-5-chlorophenyl)-3-(2-(4-((5-fluoro

1,4,5,6-tetrahydropyrimidin-2-yl)amino)-1H-indazole-6

carboxamido)acetamido)propanoic acid,

(3S)-3-(3,5-dibromophenyl)-3-(2-(4-((5-fluoro

1,4,5,6-tetrahydropyrimidin-2-yl)amino)-1H-indazole-6

carboxamido)acetamido)propanoic acid,

(3S)-3-(3-bromo-5-iodophenyl)-3-(2-(4-((5-fluoro

1,4,5,6-tetrahydropyrimidin-2-yl)amino)-1H-indazole-6

carboxamido)acetamido)propanoic acid,

(3S)-3-(3-chloro-5-iodophenyl)-3-(2-(4-((5-fluoro

1,4,5,6-tetrahydropyrimidin-2-yl)amino)-1H-indazole-6

carboxamido)acetamido)propanoic acid,

(3S)-3-(5-chloro-2-fluorophenyl)-3-(2-(4-((5-fluoro

1,4,5,6-tetrahydropyrimidin-2-yl)amino)-1H-indazole-6

carboxamido)acetamido)propanoic acid,

(3S)-3-(5-bromo-2-fluorophenyl)-3-(2-(4-((5-fluoro

1,4,5,6-tetrahydropyrimidin-2-yl)amino)-1H-indazole-6

carboxamido)acetamido)propanoic acid,

(3S)-3-(3-(difluoromethoxy)-5

(trifluoromethyl)phenyl)-3-(2-(4-((5-fluoro-1,4,5,6

tetrahydropyrimidin-2-yl)amino)-1H-indazole-6

carboxamido)acetamido)propanoic acid,

221102_G2572WO English Translation (Final) clean copy

(3S)-3-(3-chloro-5-(difluoromethoxy)phenyl)-3-(2-(4

((5-fluoro-1,4,5,6-tetrahydropyrimidin-2-yl)amino)-1H

indazole-6-carboxamido)acetamido)propanoic acid,

(3S)-3-(3-bromo-5-(difluoromethoxy)phenyl)-3-(2-(4

((5-fluoro-1,4,5,6-tetrahydropyrimidin-2-yl)amino)-1H

indazole-6-carboxamido)acetamido)propanoic acid,

(3S)-3-(3-(difluoromethoxy)-4-fluorophenyl)-3-(2-(4

((5-fluoro-1,4,5,6-tetrahydropyrimidin-2-yl)amino)-1H

indazole-6-carboxamido)acetamido)propanoic acid,

(3S)-3-(5-(difluoromethoxy)-2-fluorophenyl)-3-(2-(4

((5-fluoro-1,4,5,6-tetrahydropyrimidin-2-yl)amino)-1H

indazole-6-carboxamido)acetamido)propanoic acid,

(3S)-3-(3-(difluoromethoxy)-5-(1H-pyrazol-1

yl)phenyl)-3-(2-(4-((5-fluoro-1,4,5,6

tetrahydropyrimidin-2-yl)amino)-1H-indazole-6

carboxamido)acetamido)propanoic acid,

(3S)-3-(3,5-bis(difluoromethoxy)phenyl)-3-(2-(4-((5

fluoro-1,4,5,6-tetrahydropyrimidin-2-yl)amino)-1H

indazole-6-carboxamido)acetamido)propanoic acid,

(3S)-3-(3-chloro-5-(trifluoromethoxy)phenyl)-3-(2

(4-((5-fluoro-1,4,5,6-tetrahydropyrimidin-2-yl)amino)-1H

indazole-6-carboxamido)acetamido)propanoic acid,

(3S)-3-(3-bromo-5-(trifluoromethoxy)phenyl)-3-(2-(4

((5-fluoro-1,4,5,6-tetrahydropyrimidin-2-yl)amino)-1H

indazole-6-carboxamido)acetamido)propanoic acid,

221102_G2572WO English Translation (Final) clean copy

(3S)-3-(2-(4-((5-fluoro-1,4,5,6-tetrahydropyrimidin

2-yl)amino)-1H-indazole-6-carboxamido)acetamido)-3-(2

fluoro-5-(trifluoromethoxy)phenyl)propanoic acid,

(3S)-3-(2-(4-((5-fluoro-1,4,5,6-tetrahydropyrimidin

2-yl)amino)-1H-indazole-6-carboxamido)acetamido)-3-(4

fluoro-3-(trifluoromethoxy)phenyl)propanoic acid,

(3S)-3-(2-(4-((5-fluoro-1,4,5,6-tetrahydropyrimidin

2-yl)amino)-1H-indazole-6-carboxamido)acetamido)-3-(3

(trifluoromethyl)phenyl)propanoic acid,

(3S)-3-(2-(4-((5-fluoro-1,4,5,6-tetrahydropyrimidin

2-yl)amino)-1H-indazole-6-carboxamido)acetamido)-3-(3

(trifluoromethoxy)phenyl)propanoic acid,

(3S)-3-(3-(difluoromethoxy)phenyl)-3-(2-(4-((5

fluoro-1,4,5,6-tetrahydropyrimidin-2-yl)amino)-1H

indazole-6-carboxamido)acetamido)propanoic acid,

(3S)-3-(3-(difluoromethyl)phenyl)-3-(2-(4-((5

fluoro-1,4,5,6-tetrahydropyrimidin-2-yl)amino)-1H

indazole-6-carboxamido)acetamido)propanoic acid,

(3S)-3-(3-cyclopropylphenyl)-3-(2-(4-((5-fluoro

1,4,5,6-tetrahydropyrimidin-2-yl)amino)-1H-indazole-6

carboxamido)acetamido)propanoic acid,

(3S)-3-(3-cyclopropoxyphenyl)-3-(2-(4-((5-fluoro

1,4,5,6-tetrahydropyrimidin-2-yl)amino)-1H-indazole-6

carboxamido)acetamido)propanoic acid,

(3S)-3-(3-chlorophenyl)-3-(2-(4-((5-fluoro-1,4,5,6

tetrahydropyrimidin-2-yl)amino)-1H-indazole-6

carboxamido)acetamido)propanoic acid,

221102_G2572WO English Translation (Final) clean copy

(3S)-3-(3-bromophenyl)-3-(2-(4-((5-fluoro-1,4,5,6

tetrahydropyrimidin-2-yl)amino)-1H-indazole-6

carboxamido)acetamido)propanoic acid,

(3S)-3-(3-(1H-pyrazol-1-yl)phenyl)-3-(2-(4-((5

fluoro-1,4,5,6-tetrahydropyrimidin-2-yl)amino)-1H

indazole-6-carboxamido)acetamido)propanoic acid,

(3S)-3-(3-(3,5-dimethyl-1H-pyrazol-1-yl)phenyl)-3

(2-(4-((5-fluoro-1,4,5,6-tetrahydropyrimidin-2-yl)amino)

1H-indazole-6-carboxamido)acetamido)propanoic acid,

(3S)-3-(2-(4-((5-fluoro-1,4,5,6-tetrahydropyrimidin

2-yl)amino)-1H-indazole-6-carboxamido)acetamido)-3-(3

morpholinophenyl)propanoic acid,

(3S)-3-(4-(difluoromethoxy)phenyl)-3-(2-(4-((5

fluoro-1,4,5,6-tetrahydropyrimidin-2-yl)amino)-1H

indazole-6-carboxamido)acetamido)propanoic acid,

(3S)-3-(2-(4-((5-fluoro-1,4,5,6-tetrahydropyrimidin

2-yl)amino)-1H-indazole-6-carboxamido)acetamido)-3-(4

(trifluoromethyl)phenyl)propanoic acid,

(3S)-3-(3-chloro-5-(trifluoromethyl)phenyl)-3-(2-(3

fluoro-4-((5-fluoro-1,4,5,6-tetrahydropyrimidin-2

yl)amino)-1H-indazole-6-carboxamido)acetamido)propanoic

acid,

(3S)-3-(2-(3-chloro-4-((5-fluoro-1,4,5,6

tetrahydropyrimidin-2-yl)amino)-1H-indazole-6

carboxamido)acetamido)-3-(3-chloro-5

(trifluoromethyl)phenyl)propanoic acid,

221102_G2572WO English Translation (Final) clean copy

(3S)-3-(3-chloro-5-(trifluoromethyl)phenyl)-3-(2-(4

((5-hydroxy-1,4,5,6-tetrahydropyrimidin-2-yl)amino)-1H

indazole-6-carboxamido)acetamido)propanoic acid,

(S)-3-(3-chloro-5-(trifluoromethyl)phenyl)-3-(2-(4

((1,4,5,6-tetrahydropyrimidin-2-yl)amino)-1H-indazole-6

carboxamido)acetamido)propanoic acid,

(3S)-3-(3-chloro-5-(trifluoromethyl)phenyl)-3-(2-(6

((5-fluoro-1,4,5,6-tetrahydropyrimidin-2-yl)amino)-1H

indazole-4-carboxamido)acetamido)propanoic acid,

(3S)-3-(3-bromo-5-(trifluoromethyl)phenyl)-3-(2-(6

((5-fluoro-1,4,5,6-tetrahydropyrimidin-2-yl)amino)-1H

indazole-4-carboxamido)acetamido)propanoic acid,

(3S)-3-(2-(6-((5-fluoro-1,4,5,6-tetrahydropyrimidin

2-yl)amino)-1H-indazole-4-carboxamido)acetamido)-3-(3

iodo-5-(trifluoromethyl)phenyl)propanoic acid,

(3S)-3-(2-(6-((5-fluoro-1,4,5,6-tetrahydropyrimidin

2-yl)amino)-1H-indazole-4-carboxamido)acetamido)-3-(4

fluoro-3-(trifluoromethyl)phenyl)propanoic acid, and

(3S)-3-(2-(6-((5-fluoro-1,4,5,6-tetrahydropyrimidin

2-yl)amino)-1H-indazole-4-carboxamido)acetamido)-3-(3

(trifluoromethyl)phenyl)propanoic acid.

[0088] The compound represented by the general formula

(I) or (II) of the present invention or a

pharmaceutically acceptable salt thereof can form a

hydrate or a solvate, and each individual or a mixture

thereof is encompassed by the present invention.

221102_G2572WO English Translation (Final) clean copy

[0089] When the compound represented by the general

formula (I) or (II) of the present invention or a

pharmaceutically acceptable salt thereof has one or more

asymmetric centers, carbon-carbon double bonds, axial

chirality, or the like, optical isomers (including

enantiomers and diastereomers), geometrical isomers,

tautomers, and rotational isomers may exist. These

isomers and mixtures thereof are represented by a single

formula such as the formula (I) or (II). The present

invention encompasses each of these isomers and mixtures

(including racemates) thereof at arbitrary ratios.

[0090] In an embodiment, the compound (I) of the present

invention has both the following absolute configurations:

Y Y HN N HN N

HN HCOR and HN-f N COR

R10 A R10 A N-NH N-NH

[0091] In an embodiment, the compound (I) of the present

invention has the following absolute configuration:

Y

HN N N HN N N CO 2R

N-NH

[0092] In an embodiment, the compound (I) of the present

invention has the following absolute configuration:

221102_G2572WO English Translation (Final) clean copy

Y

HN NN HN N ' CO 2 R

/ O A R1 N-NH

[0093] Likewise, in an embodiment, the compound (II) of

the present invention has both the following absolute

configurations:

Y Y HN N H HNN O H

HN N R CO2R and HN N N COR H 0 A I H 0 A

HN-N HN-N

[0094] In an embodiment, the compound (II) of the present

invention has the following absolute configuration:

Y

HN N O H HN N - I H 0 A

HN-N

[0095] In an embodiment, the compound (II) of the present

invention has the following absolute configuration:

Y

HN NNO H HN O NNCO A 2R HN H N--j A HN-N

221102_G2572WO English Translation (Final) clean copy

[0096] A racemate can be resolved into optical

enantiomers by a method known in the art, for example,

separation of a diastereoisomeric salt thereof with an

optically active acid, and release of an optically active

amine compound by treatment with a base. Another method

for resolving a racemic compound into optical enantiomers

is based on chromatography of optically active matrix.

The compound of the present invention may also be

resolved by the formation of a diastereoisomeric

derivative. A further method for resolving optical

isomers known to those skilled in the art, such as J.

Jaques, A. Collet and S. Wilen et al., "Enantiomers,

Racemates, and Resolutions", John Wiley and Sons, New

York (1981) can be used. An optically active compound

can also be produced from an optically active starting

material.

[0097] The compound represented by the general formula

(I) or (II) of the present invention can form an acid

addition salt, etc., and such an acid-addition salt, etc.

is encompassed by the pharmaceutically acceptable salt of

the present invention.

The compound represented by the general formula (I)

or (II) of the present invention can form an acid

addition salt with an acid at an arbitrary ratio, and

each individual (e.g., monohydrochloride or

dihydrochloride) or a mixture thereof is encompassed by

the present invention. When R in the general formula (I)

221102_G2572WO English Translation (Final) clean copy

or (II) is, for example, a hydrogen atom, such a compound

can form a base-addition salt, etc., and such a base

addition salt, etc. is also encompassed by the

pharmaceutically acceptable salt of the present

invention.

[0098] The compound represented by the general formula

(I) or (II) of the present invention, when having a group

capable of forming an ester group, such as a hydroxy

group or a carboxy group, can be converted to a

pharmaceutically acceptable ester, and such a

pharmaceutically acceptable ester is encompassed by the

present invention. The pharmaceutically acceptable ester

of the compound represented by the general formula (I) or

(II) is capable of serving as a prodrug of the compound

represented by the general formula (I) or (II) and can be

hydrolyzed in a metabolic process (e.g., hydrolysis),

when administered in vivo to a subject, to form the

compound represented by the general formula (I) or (II).

[0099] The compound represented by the general formula

(I) or (II) of the present invention or a

pharmaceutically acceptable salt thereof can form an

isotope compound in which one or more atoms constituting

the compound or the salt are replaced with isotope atoms

at a non-natural ratio. The isotope atom may be

radioactive or nonradioactive and includes, for example,

heavy hydrogen ( 2 H; D), tritium ( 3 H; T), carbon-14 (14C),

and iodine-125 (125I). The radioactive or nonradioactive

221102_G2572WO English Translation (Final) clean copy

isotope compound may be used as a medicament for the

remedy or prevention of a disease, a reagent for research

(e.g., a reagent for assay), a diagnostic drug (e.g., a

diagnostic imaging drug), or the like. The present

invention encompasses such a radioactive or

nonradioactive isotope compound.

[0100] The compound represented by the general formula

(I) or (II) of the present invention or a

pharmaceutically acceptable salt thereof is capable of

inhibiting the binding of integrin av to its ligand.

In an alternative embodiment, the compound

represented by the general formula (I) or (II) of the

present invention or a pharmaceutically acceptable salt

thereof is capable of inhibiting the activation of TGF-.

TGF- participates in the differentiation, survival,

proliferation, and the like of cells and plays an

important role in development, immunity, wound healing,

and the like and therefore, is deeply involved in

diseases such as inflammation, fibrosis and cancer. TGF

$ is known to have three types of isoforms in mammals,

and TGF-1 is known as a master regulator for tissue

repair, inflammation, and fibrosis (Seminars in Cell and

Developmental Biology, 2020, 101, 123-139). TGF- is

secreted as an inactive form (latent form) and activated

by various methods so as to exhibit physiological

activity. RGD integrin including av1 and av6 is known

to play an important role in the activation of TGF-31.

221102_G2572WO English Translation (Final) clean copy

For example, an avl integrin inhibitor (Non Patent

Literature 8: Science Translational Medicine, 2015, 7

(288), 288ra79) or an av$6 integrin inhibitor (Cancer

Research, 2008, 68 (2), 561-570) inhibits the activation

of TGF-1. Thus, the compound represented by the general

formula (I) or (II) of the present invention or a

pharmaceutically acceptable salt thereof can be useful in

the prevention, alleviation and/or remedy of diseases

such as inflammatory disease, fibrosis, cancer,

neurodegenerative disease, eye disease, osteoporosis and

osteogenesis imperfecta.

In an alternative embodiment, the compound

represented by the general formula (I) or (II) of the

present invention or a pharmaceutically acceptable salt

thereof is capable of inducing the dedifferentiation of

activated human hepatic stellate cells. Stellate cells

or fibroblasts differentiate into active stellate cells

or myofibroblasts expressing a-smooth muscle actin (ax

SMA, ACTA2) through TGF-1 or the like, and enhance

collagen production, etc. For example, it has been

reported that in integrin av-knockout stellate cells, the

expression of c-SMA was suppressed and further the

production of collagen or the like was also suppressed,

because TGF-1 is not activated (Non Patent Literature

16: Nature Medicine, 2013, 19 (12), 1617-1624). Such

enhanced collagen production is seen in diseases such as

inflammation, fibrosis and cancer. Thus, the compound

221102_G2572WO English Translation (Final) clean copy

represented by the general formula (I) or (II) of the

present invention or a pharmaceutically acceptable salt

thereof can be useful in the prevention, alleviation

and/or remedy of diseases such as inflammatory disease,

fibrosis, cancer, neurodegenerative disease, eye disease,

osteoporosis and osteogenesis imperfecta.

In an alternative embodiment, the compound

represented by the general formula (I) or (II) of the

present invention or a pharmaceutically acceptable salt

thereof is capable of suppressing increase in

hydroxyproline (HYP) level which is an index for fibrosis

in non-alcoholic steatohepatitis (NASH) model animals.

Thus, the compound represented by the general formula (I)

or (II) of the present invention or a pharmaceutically

acceptable salt thereof can be useful in the prevention,

alleviation and/or remedy of non-alcoholic

steatohepatitis (NASH).

In an alternative embodiment, the compound

represented by the general formula (I) or (II) of the

present invention or a pharmaceutically acceptable salt

thereof has excellent pharmacokinetic characteristics.

The compound represented by the general formula (I) or

(II) of the present invention or a pharmaceutically

acceptable salt thereof is capable of exhibiting

excellent transcellular permeability, for example, in a

membrane permeability test using Caco2 cells. The

transcellular permeability in a membrane permeability

221102_G2572WO English Translation (Final) clean copy

test using Caco2 cells reportedly correlates with the

rate of intestinal absorption.

In an alternative embodiment, the compound

represented by the general formula (I) or (II) of the

present invention or a pharmaceutically acceptable salt

thereof has excellent safety. The compound represented

by the general formula (I) or (II) of the present

invention or a pharmaceutically acceptable salt thereof

is shown to form no or few reactive metabolites through

metabolism in liver microsomes, for example.

[0101] <Pharmaceutical composition of present invention>

In one embodiment, the present invention relates to

a pharmaceutical composition comprising the compound

represented by the general formula (I) or (II) of the

present invention or a pharmaceutically acceptable salt

thereof.

[0102] In one embodiment, the pharmaceutical composition

of the present invention can be used for the treatment of

a disease related to integrin av.

[0103] In one embodiment, the present invention relates

to use of the compound represented by the general formula

(I) or (II) of the present invention or a

pharmaceutically acceptable salt thereof for a disease

related to integrin av.

[0104] In one embodiment, the present invention relates

to the compound represented by the general formula (I) or

(II) of the present invention or a pharmaceutically

221102_G2572WO English Translation (Final) clean copy

acceptable salt thereof for use in the treatment of a

disease related to integrin av.

[0105] In one embodiment, the present invention relates

to use of the compound represented by the general formula

(I) or (II) of the present invention or a

pharmaceutically acceptable salt thereof for producing a

medicament for the treatment of a disease related to

integrin av.

[0106] In one embodiment, the present invention relates

to a method for the treatment of a disease related to

integrin av, comprising administering the compound

represented by the general formula (I) or (II) of the

present invention or a pharmaceutically acceptable salt

thereof in an amount effective for prevention,

alleviation and/or remedy to a subject.

[0107] In one embodiment of the present invention,

examples of the disease related to integrin av can

include inflammatory disease, fibrosis, cancer,

neurodegenerative disease, eye disease, osteoporosis, and

osteogenesis imperfecta.

In an alternative embodiment, the disease related to

integrin av is fibrosis.

[0108] In one embodiment, the fibrosis can be selected

from fibroses in the lung, the liver, the kidney, the

heart, vascular vessels, the skin, the pancreas, the bone

marrow, and other organs or tissues.

221102_G2572WO English Translation (Final) clean copy

In another embodiment, the fibrosis can be selected

from pulmonary fibrosis, hepatic fibrosis, renal

fibrosis, cardiac fibrosis, vascular fibrosis,

dermatofibrosis, pancreatic fibrosis, myelofibrosis and

skeletal myofibrosis.

In an alternative embodiment, the fibrosis can be

selected from pulmonary fibrosis, hepatic fibrosis, renal

fibrosis and cardiac fibrosis.

[0109] In one embodiment, the disease related to integrin

axv is idiopathic pulmonary fibrosis (IPF).

In another embodiment, the disease related to

integrin av is non-alcoholic fatty liver disease (NAFLD).

In an alternative embodiment, the disease related to

integrin av is non-alcoholic steatohepatitis (NASH).

In an alternative embodiment, the disease related to

integrin av is primary biliary cholangitis (PBC).

In an alternative embodiment, the disease related to

integrin av is primary sclerosing cholangitis (PSC).

In an alternative embodiment, the disease related to

integrin av is alcoholic steatohepatitis.

In an alternative embodiment, the disease related to

integrin av is chronic kidney disease (CKD).

In an alternative embodiment, the disease related to

integrin av is diabetic kidney disease (diabetic

nephropathy).

221102_G2572WO English Translation (Final) clean copy

In an alternative embodiment, the disease related to

integrin av is cardiac fibrosis associated with

myocardial infarction.

[0110] The subject to which the compound represented by

the general formula (I) or (II) of the present invention

or a pharmaceutically acceptable salt thereof or the

pharmaceutical composition of the present invention is

administered is a mammal. The mammal includes, for

example, a human, a monkey, a bovine, a horse, sheep, a

goat, a rabbit, a dog, a cat, a mouse, a rat, a guinea

pig or a transgenic species thereof. The compound

represented by the general formula (I) or (II) of the

present invention or a pharmaceutically acceptable salt

thereof or the pharmaceutical composition of the present

invention is preferably administered to a human.

[0111] The dose, i.e., the amount effective for

prevention, alleviation and/or remedy, of the compound

represented by the general formula (I) or (II) of the

present invention or a pharmaceutically acceptable salt

thereof may vary depending on the frequency and method of

administration, the animal species, sex, age, body weight

and general condition of a recipient, the severity of the

disease, etc., and can be appropriately set by those

skilled in the art. For oral administration as to an

adult human (60 kg), for example, 0.01 to 3000 mg,

preferably 0.1 to 600 mg, is appropriate as the dose per

day of the compound of the present invention and can be

221102_G2572WO English Translation (Final) clean copy

administered once to several times a day, for example, in

one portion or two, three or four divided portions. For

parenteral administration to an adult human, for example,

0.001 to 1000 mg, preferably 0.01 to 300 mg, is

appropriate as the dose of the compound of the present

invention and can be administered once to several times a

day, for example, in one portion or two, three or four

divided portions. For parenteral administration, the

compound of the present invention can be used at a

concentration of, for example, 0.00001% (w/v) to 10%

(w/v), preferably 0.001% (w/v) to 5% (w/v).

[0112] As for a parenteral route of intravenous,

intrathecal, intramuscular or similar administration,

etc., the dosage is typically smaller than an amount that

is used for oral administration.

[0113] The compound represented by the general formula

(I) or (II) of the present invention or a

pharmaceutically acceptable salt thereof may be

administered by single administration or multiple

administration, either singly as a pure compound or in

combination with a pharmaceutically acceptable carrier.

A pharmaceutical composition formed by combining the

compound of the present invention with a pharmaceutically

acceptable carrier may be administered in various dosage

forms suitable for administration routes. The

pharmaceutical composition according to the present

invention may be formulated together with a

221102_G2572WO English Translation (Final) clean copy

pharmaceutically acceptable carrier in accordance with a

conventional approach disclosed in, for example,

Remington: The Science and Practice of Pharmacy, 19

Edition, Gennaro, Ed., Mack Publishing Co., Easton, PA,

1995.

[0114] The pharmaceutical composition of the present

invention can be administered orally or parenterally.

The parenteral route may include, for example, rectal,

transnasal, pulmonary, transdermal, intracerebral,

intraperitoneal, vaginal, subcutaneous, intramuscular,

intrathecal, intravenous and intradermal routes. The

pharmaceutical composition of the present invention may

be specified and formulated for administration through an

arbitrary appropriate route. A preferred route may be

selected depending on the general condition and age of a

recipient, the properties of a condition to receive a

treatment, and an active ingredient selected.

[0115] The pharmaceutical composition for oral

administration includes solid preparations such as

capsules, tablets, sugar-coated tablets, pills, lozenges,

powders and granules. Such solid preparations can be

prepared in a coated form, if appropriate. Nonsolid

preparations for oral administrations include solutions

(including solutions for inhalations), emulsions,

suspensions, syrups and elixirs.

[0116] The pharmaceutical composition for parenteral

administration includes, for example, injections,

221102_G2572WO English Translation (Final) clean copy

suppositories, sprays, ointments, creams, gels,

inhalants, skin patches, and implants. The injection is

particularly suitable for intravenous, intramuscular,

subcutaneous and intraperitoneal administration. Every

sterile aqueous medium used is readily available by a

standard approach known to those skilled in the art.

[0117] In the case of preparing an oral solid

preparation, a carrier, for example, an excipient, and

optionally a binder, a disintegrant, a lubricant, a

colorant, a corrigent, and the like can be added to a

principal agent, followed by a routine method to prepare

tablets, coated tablets, granules, fine granules,

powders, capsules, or the like. An oral nonsolid

preparation such as a syrup can also be appropriately

prepared.

[0118] For example, lactose, sucrose, corn starch,

saccharose, glucose, sorbitol, crystalline cellulose, or

silicon dioxide is used as the excipient. For example,

polyvinyl alcohol, ethylcellulose, methylcellulose, gum

arabic, hydroxypropylcellulose, or

hydroxypropylmethylcellulose is used as the binder. For

example, magnesium stearate, talc, or silica is used as

the lubricant. An agent that is acceptable for addition

to medicaments is used as the colorant. For example,

cacao powder, menthol, aromatic acid, mint oil, kapur, or

powdered cinnamon bark is used as the corrigent. Such

tablets or granules may be appropriately coated, if

221102_G2572WO English Translation (Final) clean copy

necessary, with sugar, gelatin, or the like as a matter

of course.

[0119] In the case of preparing an injection, a carrier,

for example, a pH adjuster, a buffer, a suspending agent,

a solubilizer, a stabilizer, a tonicity agent, or a

preservative can be added, if necessary, to a principal

agent, followed by a routine method to prepare an

intravenous injection, a subcutaneous injection, an

intramuscular injection, or an intravenous drip infusion

agent. In this respect, a freeze-dried product may be

prepared by a routine method, if necessary.

[0120] Examples of the suspending agent can include

methylcellulose, polysorbate 80, hydroxyethylcellulose,

gum arabic, powdered tragacanth, sodium

carboxymethylcellulose, and polyoxyethylene sorbitan

monolaurate.

[0121] Examples of the solubilizer can include

polyoxyethylene hydrogenated castor oil, polysorbate 80,

nicotinamide, polyoxyethylene sorbitan monolaurate,

macrogol, castor oil fatty acid ethyl ester, and

cyclodextrin.

[0122] Examples of the stabilizer can include sodium

sulfite and sodium metasulfite. Examples of the

preservative can include methyl p-hydroxybenzoate, ethyl

p-hydroxybenzoate, sorbic acid, phenol, cresol, and

chlorocresol.

[0123] <Synthesis method>

221102_G2572WO English Translation (Final) clean copy

The compound represented by the general formula (I)

or (II) of the present invention can be produced by a

method summarized in any of reaction processes 1 to 2

given below. A modification or an alteration that is

known per se to chemists in the art or can be obvious to

those skilled in the art may be used in the methods

described below.

[0124] In the following description about production

methods, A, R, R1 and Y are as defined above, unless

otherwise specified.

[0125] <Process 1>

A compound (I) or (II) wherein R is a Ci-C6 alkyl

group can be produced through step 1 of the following

process 1.

Y Y

HN N H HN N H O H2N N CO 2 R H 0O HN OH + 0 A ' H N CO2R R 1 (3) Step 1 R0 O A N-NH N-NH

(1A) (i)

Y Y

HN-.-N 0 H HN.-N o N2 HT HN N OH H2N CO2 R HN N H 0 A + A Sep 1 1; R (3) Ste1 HN-N HN-N

(2A) (II)

[0126] Step 1 of process 1 is the step of condensing a

compound (1A) or (2A) and a compound (3) in a solvent

221102_G2572WO English Translation (Final) clean copy

using a dehydration-condensation agent to produce the

compound (I) or (II) of the present invention.

The compound (1A) or (2A) can be produced in

accordance with syntheses 1 and 2 mentioned later and the

description of Examples of the present specification.

The compound (1A) or (2A) may be an acid-addition salt,

etc. Examples of the acid-addition salt, etc. include

hydrochloride, sulfate, and acetate.

[0127] The compound (3) can also be produced in

accordance with synthesis 6 mentioned later and the

description of Examples of the present specification.

The compound (3) may be an acid-addition salt, etc.

Examples of the acid-addition salt, etc. include

hydrochloride, sulfate, and acetate.

[0128] Examples of the dehydration-condensation agent for

use in step 1 of process 1 include

dicyclohexylcarbodiimide (DCC), N,N'

diisopropylcarbodiimide (DIC), 1-(3-dimethylaminopropyl)

3-ethylcarbodiimide or hydrochloride thereof (EDC, EDAC),

N,N-dicyclohexylamide, carbonyldiimidazole, 1H

benzotriazol-1-yloxytris(dimethylamino)phosphonium

hexafluorophosphate, and 0-(7-azabenzotriazol-1-yl)

1,1,3,3-tetramethyluronium hexafluorophosphate. N,N'

Diisopropylcarbodiimide or dicyclohexylcarbodiimide is

preferred.

[0129] Step 1 of process 1 may be performed, if

necessary, in the presence of an activator such as 1

221102_G2572WO English Translation (Final) clean copy

hydroxybenzotriazole (HOBt), 1-hydroxy-7-azabenzotriazole

(HOAt), N-hydroxysuccinimide (HOSu), or 4

dimethylaminopyridine.

Step 1 of process 1 may be performed, if necessary,

in the presence of a base such as N,N

diisopropylethylamine, N-methylmorpholine, or

triethylamine.

[0130] The solvent for use in step 1 of process 1 is not

particularly limited as long as the solvent dissolves the

starting materials to some extent without inhibiting the

reaction. Examples thereof include: amides such as N,N

dimethylformamide (DMF), N,N-dimethylacetamide, and N

methylpyrrolidone; halogenated hydrocarbons such as

dichloromethane (DCM); esters such as ethyl acetate;

hydrocarbons such as dichlorohexane and n-hexane;

aromatic hydrocarbons such as toluene; ethers such as

tetrahydrofuran, diethyl ether, cyclopentyl methyl ether,

1,4-dioxane, and tert-butyl methyl ether; sulfur solvents

such as dimethyl sulfoxide (DMSO); and arbitrary mixed

solvents thereof. An aprotic polar solvent is preferred,

and N,N-dimethylformamide, dimethyl sulfoxide, or a mixed

solvent prepared by mixing them is more preferred.

[0131] The reaction temperature differs depending on the

types, usages, etc. of the starting materials, the

solvent, and the like, and is usually -20°C to 100°C,

preferably 0°C to 50°C.

221102_G2572WO English Translation (Final) clean copy

[0132] The reaction time differs depending on the

reaction temperature, etc., and is usually 10 minutes to

120 hours, preferably 30 minutes to 48 hours.

[0133] <Process 2>

A compound (I') or (II') which is a compound (I) or

(II) wherein R is a hydrogen atom can be produced by

subjecting the compound (I) or (II) produced by the

process 1 to step 2 of the following process 2.

Y Y

HN N HN N Y 0 H 0 H HN N N CO2R 3 HN N CO2H RI H 02 Step 2 RI H 02

N-NH N-NH

(1) (1)

Y Y

HN -N 0 HN N TY H 0 H HN N N CO2R 3 HN R N CO2H H0 A Step 2 H 0 A

HN-N HN-N (II) (II')

[0134] Step 2 of process 2 is the step of hydrolyzing the

ester moiety of the compound (I) or (II) or an acid

addition salt, etc. thereof in a solvent, for example,

through reaction with a base to produce a compound (I')

or (II').

[0135] Examples of the base for use in step 2 of process

2 include alkali metal hydroxide such as lithium

hydroxide, sodium hydroxide, and potassium hydroxide, and

221102_G2572WO English Translation (Final) clean copy

alkaline earth metal hydroxide such as calcium hydroxide

and magnesium hydroxide. Alkali metal hydroxide is

preferred, and lithium hydroxide or sodium hydroxide is

more preferred. These bases may each be used singly or

may be used in combination of two or more thereof. A

method for adding the base may involve adding the base in

the form of a solution containing the base dissolved in a

solvent mentioned later.

[0136] The solvent for use in step 2 of process 2 is not

particularly limited as long as the solvent dissolves the

starting materials to some extent without inhibiting the

reaction. Examples thereof include: water; amides such

as N,N-dimethylformamide, N,N-dimethylacetamide, and N

methylpyrrolidone; halogenated hydrocarbons such as

dichloromethane; hydrocarbons such as dichlorohexane and

n-hexane; aromatic hydrocarbons such as toluene; ethers

such as tetrahydrofuran, diethyl ether, cyclopentyl

methyl ether, 1,4-dioxane, and tert-butyl methyl ether;

alcohols such as methanol, ethanol, n-propanol, and

isopropanol; nitriles such as acetonitrile and

propionitrile; and arbitrary mixed solvents thereof.

Water, acetonitrile, tetrahydrofuran, N,N

dimethylformamide, methanol, ethanol, or a mixed solvent

prepared by mixing two or more of them is preferred.

[0137] The reaction temperature differs depending on the

types, usages, etc. of the starting materials, the

221102_G2572WO English Translation (Final) clean copy

solvent, and the like, and is usually -20°C to 100°C,

preferably 00C to 50°C.

[0138] The reaction time differs depending on the

reaction temperature, etc., and is usually 1 minute to 48

hours, preferably 10 minutes to 30 hours.

[0139] <Synthesis 1>

The compounds (1A) and (2A) for use as starting

materials in the process 1 mentioned above can be

produced through each step of the following synthesis 1.

221102_G2572WO English Translation (Final) clean copy

O HN S O H2N ORx CH 3NCS HN ORx

R1 R Step 3 Step 4 N-Ns 1 N-N

(1A)-1 (1A)-2

1) Mel HN S 2) NH HN 2 HN -N I OH T0 Ral \ o HN OH

N-NH Step5 N-NH (1A)-3 (1A)

H2NH H H2N ORx CH 3NCS N ORx Ri S 1 ,NN Step 3 ,N-N R/R1 g/N9 4 Step 1 N-N

(2A)-1 (2A)-2

1) Mel NH 2 H H 2) H N NOH (NH2 HN-N O S R(al S HN OH HN-N StepR5 HN-N (2A)-3 (2A)

[0140] In the formulas, P1 represents a protective group

such as a tetrahydropyranyl (THP) group.

221102_G2572WO English Translation (Final) clean copy

In the formulas, Rx is a hydrocarbon group having 1

to 6 carbon atoms, specifically, preferably a C1-C6 alkyl

group.

In the following description about production

methods, P' and Rx are as defined above unless otherwise

specified.

[0141] Step 3 of synthesis 1 is the step of reacting a

compound (1A)-1 or (2A)-1 with methyl isothiocyanate in a

solvent to obtain a compound (1A)-2 or (2A)-2.

The compound (1A)-1 or (2A)-1 is known in the art or

may be produced from another compound known in the art.

The compound can be produced, for example, in accordance

with syntheses 3 and 4 mentioned later and the

description of Examples of the present specification.

[0142] The solvent for use in step 3 of synthesis 1 is

not particularly limited as long as the solvent dissolves

the starting materials to some extent without inhibiting

the reaction. Examples thereof include: amides such as

N,N-dimethylformamide, N,N-dimethylacetamide, and N

methylpyrrolidone; halogenated hydrocarbons such as

dichloromethane; esters such as ethyl acetate;

hydrocarbons such as dichlorohexane and n-hexane;

aromatic hydrocarbons such as toluene; ethers such as

tetrahydrofuran, diethyl ether, cyclopentyl methyl ether,

1,4-dioxane, and tert-butyl methyl ether; alcohols such

as methanol, ethanol, n-propanol, and isopropanol;

nitriles such as acetonitrile and propionitrile; and

221102_G2572WO English Translation (Final) clean copy

arbitrary mixed solvents thereof. N,N-Dimethylformamide,

N-methylpyrrolidone, or methanol is preferred.

Step 3 of synthesis 1 may be performed, if

necessary, in the presence of acetic acid.

The reaction temperature differs depending on the

types, usages, etc. of the starting materials, the

solvent, and the like, and is usually 0°C to 150°C,

preferably 200C to 120°C.

The reaction time differs depending on the reaction

temperature, etc., and is usually 10 minutes to 72 hours,

preferably 30 minutes to 48 hours.

[0143] Step 4 of synthesis 1 is the step of eliminating

the protective group P' and the substituent Rx in the

compound (1A)-2 or (2A)-2 in a solvent to obtain a

compound (1A)-3 or (2A)-3.

In step 4 of synthesis 1, the protective group P'

may be eliminated first, or the substituent Rx may be

eliminated first.

[0144] When the protective group P' is, for example, a

tetrahydropyranyl group, this group can be eliminated by

preparing an acidic solution by the addition of an acid

to a solution containing the compound (1A)-2 or (2A)-2.

Examples of the acid for use in the elimination of

the protective group P' in step 4 of synthesis 1 include,

but are not particularly limited to, hydrochloric acid,

sulfuric acid, nitric acid, and trifluoroacetic acid

(TFA). These acids may each be used singly or may be

221102_G2572WO English Translation (Final) clean copy

used in combination of two or more thereof. A method for

adding the acid may involve adding the acid in the form

of a solution containing the acid dissolved in a solvent

mentioned later.

[0145] The solvent for use in the elimination of the

protective group P' in step 4 of synthesis 1 is not

particularly limited as long as the solvent dissolves the

starting materials to some extent without inhibiting the

reaction. Examples thereof include: water; amides such

as N,N-dimethylformamide, N,N-dimethylacetamide, and N

methylpyrrolidone; halogenated hydrocarbons such as

dichloromethane; aromatic hydrocarbons such as toluene;

ethers such as tetrahydrofuran, diethyl ether,

cyclopentyl methyl ether, 1,4-dioxane, and tert-butyl

methyl ether; alcohols such as methanol, ethanol, n

propanol, and isopropanol; nitriles such as acetonitrile

and propionitrile; and arbitrary mixed solvents thereof.

Water, tetrahydrofuran, dichloromethane, 1,4-dioxane,

methanol, or a mixed solvent prepared by mixing two or

more of them is preferred.

The reaction temperature differs depending on the

types, usages, etc. of the starting materials, the

solvent, and the like, and is usually -20°C to 150°C,

preferably 0°C to 100°C.

The reaction time differs depending on the reaction

temperature, etc., and is usually 10 minutes to 24 hours,

preferably 30 minutes to 10 hours.

221102_G2572WO English Translation (Final) clean copy

[0146] The substituent Rx can be eliminated by adding a

base to a solution containing the compound (1A)-2 or

(2A)-2.

Examples of the base for use in the elimination of

the substituent Rx in step 4 of synthesis 1 include

alkali metal hydroxide such as lithium hydroxide, sodium

hydroxide, and potassium hydroxide, and alkaline earth

metal hydroxide such as calcium hydroxide and magnesium

hydroxide. Alkali metal hydroxide is preferred, and

lithium hydroxide or sodium hydroxide is more preferred.

These bases may each be used singly or may be used in

combination of two or more thereof. A method for adding

the base may involve adding the base in the form of a

solution containing the base dissolved in a solvent

mentioned later.

[0147] The solvent for use in the elimination of the

substituent Rx in step 4 of synthesis 1 is not

particularly limited as long as the solvent dissolves the

starting materials to some extent without inhibiting the

reaction. Examples thereof include: water; amides such

as N,N-dimethylformamide, N,N-dimethylacetamide, and N

methylpyrrolidone; ethers such as tetrahydrofuran,

diethyl ether, cyclopentyl methyl ether, 1,4-dioxane, and

tert-butyl methyl ether; alcohols such as methanol,

ethanol, n-propanol, and isopropanol; nitriles such as

acetonitrile and propionitrile; and arbitrary mixed

solvents thereof. Water, tetrahydrofuran, methanol, or a

221102_G2572WO English Translation (Final) clean copy

mixed solvent prepared by mixing two or more of them is

preferred.

The reaction temperature differs depending on the

types, usages, etc. of the starting materials, the

solvent, and the like, and is usually -20°C to 100°C,

preferably 00C to 50°C.

The reaction time differs depending on the reaction

temperature, etc., and is usually 10 minutes to 24 hours,

preferably 30 minutes to 10 hours.

[0148] Step 5 of synthesis 1 is the step of reacting the

compound (1A)-3 or (2A)-3 with methyl iodide

(iodomethane) which is a methylating agent in reaction of

the first stage and with diamine of the compound (al) or

an acid-addition salt, etc. thereof in reaction of the

second stage in a solvent to obtain a compound (1A) or

(2A).

The solvent for use at the first stage in step 5 of

synthesis 1 is not particularly limited as long as the

solvent dissolves the starting materials to some extent

without inhibiting the reaction. Examples thereof

include: amides such as N,N-dimethylformamide, N,N

dimethylacetamide, and N-methylpyrrolidone; halogenated

hydrocarbons such as dichloromethane; esters such as

ethyl acetate; hydrocarbons such as dichlorohexane and n

hexane; aromatic hydrocarbons such as toluene; ethers

such as tetrahydrofuran, diethyl ether, cyclopentyl

methyl ether, 1,4-dioxane, and tert-butyl methyl ether;

221102_G2572WO English Translation (Final) clean copy

and arbitrary mixed solvents thereof. N,N

Dimethylformamide or N-methylpyrrolidone is preferred.

The reaction temperature differs depending on the

types, usages, etc. of the starting materials, the

solvent, and the like, and is usually 00C to 150°C,

preferably 100C to 1200C, more preferably 200C to 50°C.

The reaction time differs depending on the reaction

temperature, etc., and is usually 1 minute to 48 hours,

preferably 10 minutes to 24 hours.

[0149] At the second stage in step 5 of synthesis 1, a

compound (1A) or (2A) is produced through reaction with

diamine of the compound (al) or an acid-addition salt,

etc. thereof in the presence or absence of water. The

compound (al) may be an acid-addition salt, etc.

Examples of the acid-addition salt, etc. include

hydrochloride, sulfate, and acetate.

The reaction temperature differs depending on the

types, usages, etc. of the starting materials, the

solvent, and the like, and is usually 00C to 150°C,

preferably 200C to 120°C.

The reaction time differs depending on the reaction

temperature, etc., and is usually 10 minutes to 48 hours,

preferably 30 minutes to 24 hours.

[0150] Both the protective group P' and the substituent Rx

in the compound (1A)-2 or (2A)-2 are eliminated in a

solvent in step 4 of synthesis 1, and then, step 5 is

performed to produce a compound (1A) or (2A).

221102_G2572WO English Translation (Final) clean copy

Alternatively, as shown below, the substituent Rx in the

compound (1A)-2 may be eliminated to prepare a compound

(1A)-3' (step 4a), followed by the step 5 mentioned above

to prepare a compound (1A)-4, and then, the protective

group P1 can be eliminated to produce a compound (1A)

(step 4b). The compound (2A) can also be produced by the

same scheme as described below.

[0151]

1) Mel NH2 HN S O HN S O 2) NH 2 HN HNHY HN ORx HN OH (al)

Step 4a R 1 Step 5 N-N N-N, 1

(1A)-2 (1A)-3' Y Y

HN N HN O HN zN HN 0 HN OH HN OH

R Step 4b R N-Np 1 N-NH

(1A)-4 (1A)

[0152] In the scheme, the same methods as in step 4 can

be applied to a method for eliminating the substituent Rx

in step 4a, and a method for eliminating the protective

group P1 in step 4b.

[0153] <Synthesis 2>

In synthesis 1, the compound (1A) or (2A) is

produced using the compound (1A)-1 or (2A)-1 in which the

221102_G2572WO English Translation (Final) clean copy

amino group of the 5-membered heterocyclic ring is

protected with the protective group P1. This compound

may be produced using a compound that is not protected

with the protective group P1.

For example, the compound (1A) may be produced

through each step of synthesis 2 given below using a

compound (1A)-1'. The compound (2A) can also be produced

by the same scheme as in the following synthesis 2.

0 HN S O H 2N ORx CH 3NCS ORx

N-NH Step 3 N-NH Step 4a

(1A)- 1' (1 A)-2' 1) Mel

2)-1 HN S 2 HNH 2 HNN HN 1 OH (al) 2 HN OH

N-NH St 5 R O N-NH (1A)-3 (1A)

[0154] Step 3 and step 5 of synthesis 2 are the same as

step 3 and step 5 of synthesis 1.

Step 4a of synthesis 2 is the step of eliminating

the substituent Rx in the compound (1A)-2' or (2A)-2' in

a solvent to obtain a compound (1A) -3 or (2A) -3. Unlike

step 4 of synthesis 1, only the operation of eliminating

the substituent Rx is performed in step 4a of synthesis

2.

221102_G2572WO English Translation (Final) clean copy

The substituent Rx can be eliminated by adding a

base, as in the method for eliminating the substituent Rx

in step 4 of the synthesis 1 mentioned above. The type

of the base for use in step 4a of synthesis 2 and a

method for adding the base are the same as in the method

for eliminating the substituent Rx in step 4 of the

synthesis 1 mentioned above.

[0155] <Synthesis 3>

The compound (lA)-1 for use as a starting material

in the synthesis 1 mentioned above can be produced

through steps 6 to 8 of synthesis 3 given below. The

compound (2A)-1 can also be produced by the same scheme

as in the following synthesis 3.

0 0 Ph NH

R ~ORX ZR ORX Ph

Step Step N-NH N-N

(1A)-1-1(1A)-1-2 Ph Ph Y 0 0 N ORX H 2N ORX

R1 V3) R1 N--N P1 Step8 N-N

(1A)-1-3 (1A)-1

[0156] In the formulas, Z is a chlorine atom, a bromine

atom, or an iodine atom.

[0157] Step 6 of synthesis 3 is the step of introducing

the protective group P1 to the amino structure moiety of

the 5-membered heterocyclic ring of a compound (1A)-1-1

221102_G2572WO English Translation (Final) clean copy

in a solvent to obtain a compound (1A)-1-2. The compound

(1A)-1-1 is known in the art or may be produced from

another compound known in the art.

A method known in the art can be used as a method

for introducing the protective group P'. The method can

be performed in accordance with, for example, a method

described in Org. Biomol. Chem., 2017, 15, 8614-8626, or

J. Org. Chem., 2015, 80, 7713-7726. Specifically, the

protective group can be introduced to the amino structure

moiety using a compound corresponding to the protective

group to be introduced.

When the protective group PI is, for example, a

tetrahydropyranyl group, the tetrahydropyranyl group can

be introduced to the amino structure moiety of the 5

membered heterocyclic ring through reaction with

dihydropyran (DHP) in the presence of an acid catalyst

(p-toluenesulfonic acid, etc.).

[0158] The solvent for use in step 6 of synthesis 3 is

not particularly limited as long as the solvent dissolves

the starting materials to some extent without inhibiting

the reaction. Examples thereof include: amides such as

N,N-dimethylformamide, N,N-dimethylacetamide, and N

methylpyrrolidone; halogenated hydrocarbons such as

dichloromethane; esters such as ethyl acetate;

hydrocarbons such as dichlorohexane and n-hexane;

aromatic hydrocarbons such as toluene and xylene; ethers

such as tetrahydrofuran, diethyl ether, cyclopentyl

221102_G2572WO English Translation (Final) clean copy

methyl ether, 1,4-dioxane, and tert-butyl methyl ether;

and arbitrary mixed solvents thereof. Dichloromethane,

toluene, xylene, or tetrahydrofuran is preferred.

The reaction temperature differs depending on the

types, usages, etc. of the starting materials, the

solvent, and the like, and is usually 0°C to 150°C,

preferably 00C to 50°C.

The reaction time differs depending on the reaction

temperature, etc., and is usually 10 minutes to 48 hours,

preferably 30 minutes to 24 hours.

[0159] Step 7 of synthesis 3 is the step of reacting the

compound (1A)-1-2 with benzophenone imine in the presence

of a catalyst in a solvent under a stream of an inert gas

to obtain a compound (1A)-1-3.

Examples of the catalyst for use in step 7 of

synthesis 3 include organic palladium complexes such as

tris(dibenzylideneacetone)dipalladium and palladium

acetate.

[0160] In step 7 of synthesis 3, the reaction may be

performed in the presence of a ligand or may be performed

in the absence of a ligand.

Examples of the ligand for use in step 7 of

synthesis 3 include 4,5'-bis(diphenylphosphino)-9,9'

dimethylxanthene (Xantphos) and 2,2'

bis(diphenylphosphino)-1,1'-binaphthyl (BINAP).

221102_G2572WO English Translation (Final) clean copy

[0161] In step 7 of synthesis 3, the reaction may be

performed in the presence of a base or may be performed

in the absence of a base.

Examples of the base for use in step 7 of synthesis

3 include: alkali metal carbonate such as cesium

carbonate, potassium carbonate, sodium carbonate, and

sodium bicarbonate; alkali metal phosphate such as

tribasic potassium phosphate, sodium phosphate, and

sodium biphosphate; alkali metal fluoride such as cesium

fluoride and potassium fluoride; alkylamines such as

triethylamine and N,N-diisopropylethylamine; pyridines

such as pyridine and 4-dimethylaminopyridine; and 1,8

diazabicyclo[5.4.0]-7-undecene. Alkali metal carbonate

is preferred, and cesium carbonate is more preferred.

These bases may each be used singly or may be used in

combination of two or more thereof. A method for adding

the base may involve adding the base in the form of a

solution containing the base dissolved in a solvent

mentioned later.

[0162] The solvent for use in step 7 of synthesis 3 is

not particularly limited as long as the solvent dissolves

the starting materials to some extent without inhibiting

the reaction. Examples thereof include: water; amides

such as N,N-dimethylformamide, N,N-dimethylacetamide, and

N-methylpyrrolidone; halogenated hydrocarbons such as

dichloromethane; esters such as ethyl acetate;

hydrocarbons such as dichlorohexane and n-hexane;

221102_G2572WO English Translation (Final) clean copy

aromatic hydrocarbons such as toluene and xylene; ethers

such as tetrahydrofuran, diethyl ether, cyclopentyl

methyl ether, 1,4-dioxane, and tert-butyl methyl ether;

and arbitrary mixed solvents thereof. Toluene, xylene,

or 1,4-dioxane is preferred.

Examples of the inert gas used include nitrogen gas

and argon gas.

The reaction temperature differs depending on the

types, usages, etc. of the starting materials, the

solvent, and the like, and is usually 500C to 250°C,

preferably 700C to 200°C.

The reaction time differs depending on the reaction

temperature, etc., and is usually 1 hour to 48 hours,

preferably 3 hours to 24 hours.

[0163] Step 8 of synthesis 3 is the step of obtaining a

compound (1A)-1 from the compound (1A)-1-3.

A method for obtaining the compound (1A)-1 in step 8

can involve obtaining the compound (1A)-1 through the

reductive reaction of the compound (1A)-1-3 in the

presence of a metal catalyst and in the presence of

hydrogen gas in a solvent.

Examples of the metal catalyst for use in step 8 of

synthesis 3 include inhomogeneous catalysts such as Pd-C

catalysts, palladium hydroxide catalysts, Pt-C catalysts,

and platinum oxide catalysts.

The solvent for use in step 8 of synthesis 3 is not

particularly limited as long as the solvent dissolves the

221102_G2572WO English Translation (Final) clean copy

starting materials to some extent without inhibiting the

reaction. Examples thereof include: water; acetic acid;

amides such as N,N-dimethylformamide, N,N

dimethylacetamide, and N-methylpyrrolidone; esters such

as ethyl acetate; hydrocarbons such as dichlorohexane and

n-hexane; aromatic hydrocarbons such as toluene and

xylene; ethers such as tetrahydrofuran, diethyl ether,

cyclopentyl methyl ether, 1,4-dioxane, and tert-butyl

methyl ether; alcohols such as methanol, ethanol, n

propanol, and isopropanol; nitriles such as acetonitrile

and propionitrile; and arbitrary mixed solvents thereof.

Ethyl acetate, tetrahydrofuran, or methanol is preferred.

The reaction temperature differs depending on the

types, usages, etc. of the starting materials, the

solvent, and the like, and is usually 0°C to 150°C,

preferably 200C to 100°C.

The reaction time differs depending on the reaction

temperature, etc., and is usually 10 minutes to 120

hours, preferably 30 minutes to 48 hours.

[0164] In step 8, the compound (1A)-1 may be obtained by

hydrolyzing the compound (1A)-1-3 by the addition of an

acid (e.g., citric acid) solution to a solution

containing the compound (1A)-1-3.

The solvent for use in step 8 of synthesis 3 is not

particularly limited as long as the solvent dissolves the

starting materials to some extent without inhibiting the

reaction. Examples thereof include: water; amides such

221102_G2572WO English Translation (Final) clean copy

as N,N-dimethylformamide, N,N-dimethylacetamide, and N

methylpyrrolidone; esters such as ethyl acetate;

hydrocarbons such as dichlorohexane and n-hexane;

aromatic hydrocarbons such as toluene and xylene; ethers

such as tetrahydrofuran, diethyl ether, cyclopentyl

methyl ether, 1,4-dioxane, and tert-butyl methyl ether;

alcohols such as methanol, ethanol, n-propanol, and

isopropanol; nitriles such as acetonitrile and

propionitrile; and arbitrary mixed solvents thereof.

Tetrahydrofuran is preferred.

The reaction temperature differs depending on the

types, usages, etc. of the starting materials, the

solvent, and the like, and is usually 0°C to 200°C,

preferably 00C to 100°C.

The reaction time differs depending on the reaction

temperature, etc., and is usually 10 minutes to 120

hours, preferably 30 minutes to 48 hours.

[0165] <Synthesis 4>

The compound (1A)-1 for use as a starting material

in the synthesis 1 mentioned above may be produced

through each step of synthesis 4 given below using a

compound (1A)-1-4 given below, in addition to the

synthesis 3 mentioned above. The compound (2A)-1 can

also be produced by the same scheme as in the following

synthesis 4.

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0 0 0 02N ORX 0 2N ORx H2 N ORX

R1 1 R1 3W R1 N-NH Step 9 N-N Step10 N-N. 1

(1 A)- 1-4 (1 A)-1 -5 (1A)- 1

[0166] Step 9 of synthesis 4 is the step of introducing

the protective group P1 to the amino structure moiety of

the 5-membered heterocyclic ring of a compound (1A)-1-4

in a solvent to obtain a compound (1A)-1-5. The compound

(1A)-1-4 is known in the art or may be produced from

another compound known in the art. The same method as in

step 6 of the synthesis 3 mentioned above can be adopted

as a method for introducing the protective group P1 in

step 9. The solvent used is also the same as that used

in step 6 of synthesis 3.

[0167] Step 10 of synthesis 4 is the step of reducing the

nitro group of the compound (1A)-1-5 into an amino group

to obtain a compound (1A)-1.

In step 10 of synthesis 4, a method for reducing the

nitro group of the compound (1A)-1-5 into an amino group

to obtain a compound (1A)-1 can involve reducing the

nitro group of the compound (1A)-1-5 into an amino group

through the reductive reaction of the compound (1A)-1-5

in the presence of a reducing agent such as sodium

dithionite in a solvent to obtain a compound (1A)-1.

The solvent for use in step 10 of synthesis 4 using

a reducing agent is not particularly limited as long as

221102_G2572WO English Translation (Final) clean copy

the solvent dissolves the starting materials to some

extent without inhibiting the reaction. Examples thereof

include: water; acetic acid; amides such as N,N

dimethylformamide, N,N-dimethylacetamide, and N

methylpyrrolidone; esters such as ethyl acetate; ethers

such as tetrahydrofuran, diethyl ether, cyclopentyl

methyl ether, 1,4-dioxane, and tert-butyl methyl ether;

alcohols such as methanol, ethanol, n-propanol, and

isopropanol; nitriles such as acetonitrile and

propionitrile; and arbitrary mixed solvents thereof.

Water or ethanol is preferred.

The reaction temperature differs depending on the

types, usages, etc. of the starting materials, the

solvent, and the like, and is usually 0°C to 200°C,

preferably 500C to 150°C.

The reaction time differs depending on the reaction

temperature, etc., and is usually 10 minutes to 48 hours,

preferably 30 minutes to 24 hours.

[0168] In step 10, the compound (1A)-1 may be obtained by

reducing the nitro group of compound (1A)-1-5 into an

amino group through the reductive reaction of the

compound (1A)-1-5 in the presence of a metal catalyst and

in the presence of hydrogen gas in a solvent.

In this case, examples of the metal catalyst used

include inhomogeneous catalysts such as Pd-C catalysts,

palladium hydroxide catalysts, Pt-C catalysts, and

platinum oxide catalysts.

221102_G2572WO English Translation (Final) clean copy

The solvent for use in step 10 of synthesis 4 using

a metal catalyst is not particularly limited as long as

the solvent dissolves the starting materials to some

extent without inhibiting the reaction. Examples thereof

include: water; acetic acid; amides such as N,N

dimethylformamide, N,N-dimethylacetamide, and N

methylpyrrolidone; esters such as ethyl acetate; ethers

such as tetrahydrofuran, diethyl ether, cyclopentyl

methyl ether, 1,4-dioxane, and tert-butyl methyl ether;

alcohols such as methanol, ethanol, n-propanol, and

isopropanol; nitriles such as acetonitrile and

propionitrile; and arbitrary mixed solvents thereof.

Acetic acid or tetrahydrofuran is preferred.

The reaction temperature differs depending on the

types, usages, etc. of the starting materials, the

solvent, and the like, and is usually 0°C to 200°C,

preferably 200C to 100°C.

The reaction time differs depending on the reaction

temperature, etc., and is usually 10 minutes to 48 hours,

preferably 30 minutes to 24 hours.

[0169] <Synthesis 5>

A compound (4)-S which is an S form of the compound

(4) for use as a starting material in the process 1

mentioned above, wherein R is a C1-C6 alkyl group can be

produced through steps 11 to 13 of synthesis 5 given

below. The compound (4)-S is included in the compound

(4).

221102_G2572WO English Translation (Final) clean copy

0 ||

H2N Step 9 O BrZn CO 2 RStep 10 11 (a4) -S., (a5) A-CHO3 3 Step 11 A Step 12 (4)-1 (4)-S-1

So H2N COR 0 A Step 13 A

(4)-S-2 (4)-S

[0170] Step 11 of synthesis 5 is the step of reacting a

compound (4)-i with (R)-2-methylpropane-2-sulfinamide of

a compound (a4) in the presence of pyrrolidine and a

molecular sieve (4 angstroms) in a solvent to obtain a

compound (4)-S-1.

The solvent for use in step 11 of synthesis 5 is not

particularly limited as long as the solvent dissolves the

starting materials to some extent without inhibiting the

reaction. Examples thereof include: halogenated

hydrocarbons such as dichloromethane (DCM); aromatic

hydrocarbons such as toluene and xylene; ethers such as

tetrahydrofuran, diethyl ether, cyclopentyl methyl ether,

1,4-dioxane, and tert-butyl methyl ether; and arbitrary

mixed solvents thereof. Toluene or tetrahydrofuran is

preferred.

The reaction temperature differs depending on the

types, usages, etc. of the starting materials, the

221102_G2572WO English Translation (Final) clean copy

solvent, and the like, and is usually -20°C to 150°C,

preferably 0°C to 120°C.

The reaction time differs depending on the reaction

temperature, etc., and is usually 10 minutes to 48 hours,

preferably 30 minutes to 24 hours.

[0171] Step 12 of synthesis 5 is the step of reacting the

compound (4)-S-1 with a compound (a5) in a solvent to

obtain a compound (4)-S-2.

The compound (a5) used is a compound corresponding

to R of the compound (4)-S of interest. The compound

(a5) is known in the art, or can be produced from a

compound known in the art in accordance with the

description of Examples of the present specification

mentioned later.

Specific examples of the compound (a5) include (2

methoxy-2-oxoethyl)zinc(II) bromide, (2-ethoxy-2

oxoethyl)zinc(II) bromide, (2-isopropoxy-2

oxoethyl)zinc(II) bromide, and [2-(tert-butoxy)-2

oxoethyl]zinc(II) bromide.

[0172] The solvent for use in step 12 of synthesis 5 is

not particularly limited as long as the solvent dissolves

the starting materials to some extent without inhibiting

the reaction. Examples thereof include: halogenated

hydrocarbons such as dichloromethane (DCM); aromatic

hydrocarbons such as toluene; ethers such as

tetrahydrofuran, diethyl ether, cyclopentyl methyl ether,

221102_G2572WO English Translation (Final) clean copy

1,4-dioxane, and tert-butyl methyl ether; and arbitrary

mixed solvents thereof. Tetrahydrofuran is preferred.

The reaction temperature differs depending on the

types, usages, etc. of the starting materials, the

solvent, and the like, and is usually -78°C to 100°C,

preferably -20°C to 50°C.

The reaction time differs depending on the reaction

temperature, etc., and is usually 10 minutes to 48 hours,

preferably 30 minutes to 24 hours.

[0173] Step 13 of synthesis 5 is the step of reacting the

compound (4)-S-2 with an acid in a solvent to obtain a

compound (4)-S.

Examples of the acid for use in step 13 of synthesis

include: organic acids such as acetic acid, formic

acid, trifluoroacetic acid, and p-toluenesulfonic acid;

and inorganic acids such as hydrochloric acid,

hydrobromic acid, and sulfuric acid. Hydrochloric acid

is preferred. These acids may each be used singly or may

be used in combination of two or more thereof. A method

for adding the acid may involve adding the acid in the

form of a solution containing the acid dissolved in a

solvent mentioned later.

[0174] The solvent for use in step 13 of synthesis 5 is

not particularly limited as long as the solvent dissolves

the starting materials to some extent without inhibiting

the reaction. Examples thereof include: water; alcohols

such as methanol and ethanol; halogenated hydrocarbons

221102_G2572WO English Translation (Final) clean copy

such as dichloromethane (DCM); aromatic hydrocarbons such

as toluene; ethers such as tetrahydrofuran, diethyl

ether, cyclopentyl methyl ether, 1,4-dioxane, and tert

butyl methyl ether; and arbitrary mixed solvents thereof.

An ether, an alcohol or an arbitrary mixed solvent

thereof is preferred.

The reaction temperature differs depending on the

types, usages, etc. of the starting materials, the

solvent, and the like, and is usually -20°C to 100°C,

preferably 00C to 50°C.

The reaction time differs depending on the reaction

temperature, etc., and is usually 1 minute to 48 hours,

preferably 10 minutes to 24 hours.

The compound (4)-S thus obtained may be an acid

addition salt, etc. Examples of the acid-addition salt,

etc. include hydrochloride, sulfate, and acetate.

[0175] As described above, the compound (4)-S can be

synthesized through steps 11 to 13 of synthesis 5. An

asymmetric compound opposite to the compound (4)-S can be

synthesized through steps 11 to 13 using, for example,

(S)-2-methylpropane-2-sulfinamide, instead of the

compound (a4). Further, a racemate of the compound (4)-S

can be synthesized through steps 11 to 13 using, for

example, racemic 2-methylpropane-2-sulfinamide, instead

of the compound (a4).

[0176] <Synthesis 6>

221102_G2572WO English Translation (Final) clean copy

The compound (3) for use as a starting material in

the process 1 mentioned above, wherein R is a Ci-C6 alkyl

group can be produced through steps 14 and 15 of the

following synthesis 6.

H 2 p OH H H H 2N CO 2 R (a6) P N CO2R H2N N CO2R A Step 4 0 A Step 15 0 A

(4) (3)-i (3)

[0177] Step 14 of synthesis 6 is the step of reacting the

compound (4) obtained by a method such as synthesis 5 or

an acid-addition salt, etc. thereof with a compound (a6)

in the presence of a dehydration-condensation agent in a

solvent to obtain a compound (3)-1.

In the formulas, P 2 represents a protective group

such as a t-butoxycarbonyl group (Boc).

[0178] Examples of the dehydration-condensation agent for

use in step 14 of synthesis 6 include

dicyclohexylcarbodiimide (DCC), N,N'

diisopropylcarbodiimide (DIC), 1-(3-dimethylaminopropyl)

3-ethylcarbodiimide or hydrochloride thereof (EDC, EDAC),

N,N-dicyclohexylamide, 1-hydroxybenzotriazole,

carbonyldiimidazole, 1H-benzotriazol-1

yloxytris(dimethylamino)phosphonium hexafluorophosphate,

and O-(7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyluronium

hexafluorophosphate. 1-(3-Dimethylaminopropyl)-3

ethylcarbodiimide or hydrochloride thereof (EDC, EDAC) is

preferred.

221102_G2572WO English Translation (Final) clean copy

[0179] In step 14 of synthesis 6, the reaction may be

performed in the presence of a base or may be performed

in the absence of a base.

Examples of the base for use in step 14 of synthesis

6 include N,N-diisopropylethylamine, N-methylmorpholine,

triethylamine, 4-(N,N-dimethylamino)pyridine, and N

ethyl-N-isopropylpropan-2-amine. N,N

Diisopropylethylamine or triethylamine is preferred.

These bases may each be used singly or may be used in

combination of two or more thereof. A method for adding

the base may involve adding the base in the form of a

solution containing the base dissolved in a solvent

mentioned later.

[0180] The solvent for use in step 14 of synthesis 6 is

not particularly limited as long as the solvent dissolves

the starting materials to some extent without inhibiting

the reaction. Examples thereof include: amides such as

N,N-dimethylformamide (DMF), N,N-dimethylacetamide, and

N-methylpyrrolidone; halogenated hydrocarbons such as

dichloromethane (DCM); esters such as ethyl acetate;

hydrocarbons such as dichlorohexane and n-hexane;

aromatic hydrocarbons such as toluene; ethers such as

tetrahydrofuran, diethyl ether, cyclopentyl methyl ether,

1,4-dioxane, and tert-butyl methyl ether; and arbitrary

mixed solvents thereof. Dichloromethane is preferred.

The reaction temperature differs depending on the

types, usages, etc. of the starting materials, the

221102_G2572WO English Translation (Final) clean copy

solvent, and the like, and is usually -20°C to 100°C,

preferably 00C to 50°C.

The reaction time differs depending on the reaction

temperature, etc., and is usually 10 minutes to 72 hours,

preferably 30 minutes to 48 hours.

[0181] Step 15 of synthesis 6 is the step of deprotecting

the protective group P 2 from the compound (3)-1 using an

acid in a solvent to obtain a compound (3).

Examples of the acid for use in step 15 of synthesis

6 include: organic acids such as acetic acid, formic

acid, trifluoroacetic acid, and p-toluenesulfonic acid;

and inorganic acids such as hydrochloric acid,

hydrobromic acid, and sulfuric acid. Hydrochloric acid

is preferred. These acids may each be used singly or may

be used in combination of two or more thereof. A method

for adding the acid may involve adding the acid in the

form of a solution containing the acid dissolved in a

solvent mentioned later.

[0182] The solvent for use in step 15 of synthesis 6 is

not particularly limited as long as the solvent dissolves

the starting materials to some extent without inhibiting

the reaction. Examples thereof include: water; alcohols

such as methanol and ethanol; halogenated hydrocarbons

such as dichloromethane (DCM); aromatic hydrocarbons such

as benzene, toluene, and xylene; ethers such as

tetrahydrofuran, diethyl ether, cyclopentyl methyl ether,

1,4-dioxane, and tert-butyl methyl ether; nitriles such

221102_G2572WO English Translation (Final) clean copy

as acetonitrile and propionitrile; and arbitrary mixed

solvents thereof. An ether, an alcohol or an arbitrary

mixed solvent thereof is preferred.

The reaction temperature differs depending on the

types, usages, etc. of the starting materials, the

solvent, and the like, and is usually -20°C to 100°C,

preferably 00C to 50°C.

The reaction time differs depending on the reaction

temperature, etc., and is usually 10 minutes to 72 hours,

preferably 30 minutes to 48 hours.

The compound (3) thus obtained may be an acid

addition salt, etc. Examples of the acid-addition salt,

etc. include hydrochloride, sulfate, and acetate.

[0183] In the present specification, the obtained

compound in each step may be isolated or purified by an

approach known in the art or may be subjected directly to

a subsequent step. The isolation or the purification can

be carried out by use of a usual operation, for example,

filtration, extraction, crystallization, or each column

chromatography.

[0184] <Intermediate of present invention>

In one embodiment of the present invention,

compounds given below which are intermediates of the

compound (I) or (II) or a pharmaceutically acceptable

salt thereof are also included in the present invention.

In one embodiment, examples of the intermediate of

the present invention include compounds represented by

221102_G2572WO English Translation (Final) clean copy

the following general formula (X-1) or (X-2) and salts

thereof:

RY 0 RY 0 HN HN HN ORXA HN ORXA

N-N Rz Rz' N-N

(X-1) (X-2)

In the formulas (X-1) and (X-2), RY is a group

represented by the following formula (x)-i or (x)-ii:

Y

HN 1-N HN S

(x)-i (x)-ii wherein Y is a hydrogen atom, a fluorine atom or a

hydroxy group, as in the general formulas (I) and (II),

R7 is a C1-C6 alkyl group, and * represents a binding

position.

R' is a hydrogen atom or a halogen atom, as in the

general formulas (I) and (II).

RXA is a hydrogen atom or a hydrocarbon group having

1 to 6 carbon atoms and is preferably a hydrogen atom or

a C1-C6 alkyl group.

221102_G2572WO English Translation (Final) clean copy

Rz is a hydrogen atom or P' (wherein P' represents,

as mentioned above, a protective group such as a

tetrahydropyranyl (THP) group).

[0185] In one embodiment, RY in the general formula (X-1)

is a group represented by the formula (x)-i.

In one embodiment, RY in the general formula (X-1)

is a group represented by the formula (x)-ii.

In one embodiment, RY in the general formula (X-2)

is a group represented by the formula (x)-i.

In one embodiment, RY in the general formula (X-2)

is a group represented by the formula (x)-ii.

[0186] In one embodiment, examples of the intermediate of

the present invention include compounds represented by

the following general formula (X-1-1) or (X-2-1) and

salts thereof:

RYA O RYA O HN ORXA1 HN ORXA1

R1A R 1A

N-N N-N R RZA

(X-1-1) (X-2-1) In the formulas (X-1-1) and (X-2-1), RYA is a group

represented by the following formula (x)-i-1, (x)-i-2,

(x)-i-3, or (x)-ii-1:

221102_G2572WO English Translation (Final) clean copy

F OH HN N HN N HN N HN S * * *

* (x)-i-1 (x)-i-2 (x)-i-3 ()i wherein * represents a binding position.

RlA is a hydrogen atom, a fluorine atom, or a

chlorine atom.

RXAl is a hydrogen atom or a methyl group.

RZA is a hydrogen atom or a tetrahydropyranyl (THP)

group.

[0187] In one embodiment, RYA in the general formula (X-1

1) is a group represented by the formula (x)-i-1, the

formula (x)-i-2, or the formula (x)-i-3.

In one embodiment, RYA in the general formula (X-1-1)

is a group represented by the formula (x)-ii-1.

In one embodiment, RYA in the general formula (X-2-1)

is a group represented by the formula (x)-i-1, the

formula (x)-i-2, or the formula (x)-i-3.

In one embodiment, RYA in the general formula (X-2-1)

is a group represented by the formula (x)-ii-1.

[0188] In one embodiment, examples of the intermediate of

the present invention include compounds selected from the

following group and salts thereof:

221102_G2572W0 English Translation (Final) clean copy

HN 'rS HN

HN ~ N HN S

FN N~-H HNSHH

HN SHN, HN.,S

N-N N-NN HN X C1 F N-HN-NH N-NH

HN N HNNSNNH HN 0 T 0 HN-SNN H OHHN CHHN OH 0 T N~ H O N O "OH HNH HN~OH C1F FP N-NH N-NO N-NHn N-HCNHNN

00 F

HN S0N~ HN N

01HN11I OH [I OH

[0189] In one embodiment, the intermediate of the present

invention is a compound selected from the following group

or a salt thereof:

HN 1 S .- rN S H 0, HN S HN HN HN aa0 I FoHNl HN 11 HN 01

N-N N-NO N-N C1 F N-NH N-NH N-NH

HN HNS HN S 00 HN S HN SHN S HN OH OH OH HN OH HN 0 OHH0

K11 F KIl KIl OH HO HN OH

0 N-NO N-Nn N-NO C1 F

0 NH N-NH N-NH

221102_G2572WO English Translation (Final) clean copy

[0190] In one embodiment, the intermediate of the present

invention is a compound selected from the following group

or a salt thereof:

F F F F OH

HNrN O HN N O HNrN O HN N O HNrN O HNrN O

OH H OH HN OH HN OH HN OH ci OH F C,: F \ A F P N-NH N-N N-NH N-NH N-NH N-NH

[0191] In one embodiment, the intermediate of the present

invention is a compound selected from the following group

or a salt thereof:

F HN S O HN S HN N HN O HN OH HN OH HN-N HN-N HN-N

[0192] In another embodiment, examples of the

intermediate of the present invention include compounds

represented by the following general formula (X-3) and

salts thereof:

H RW N NC2 H CO 2 R 0 A (X-3)

In the formula (X-3), A is a C6-C1O aryl group or a

heteroaryl group, wherein at least one hydrogen atom of

the aryl group or the heteroaryl group is optionally

221102_G2572WO English Translation (Final) clean copy

replaced with a substituent selected from the group

consisting of a halogen atom, a hydroxy group, a C1-C6

alkyl group, a C1-C6 haloalkyl group, a C2-C6 alkenyl

group, a C2-C6 alkynyl group, a C1-C6 alkoxy group, a C1-C6

haloalkoxy group, a C3-C6 cycloalkyl group, a C3-C6

cycloalkenyl group, a C3-C6 cycloalkoxy group, a

heterocyclyl group, a heteroaryl group optionally

substituted by a C1-C6 alkyl group, a cyano group, a

carboxyl group, a carbamoyl group, a C1-C6 alkoxycarbonyl

group, a C1-C6 alkylsulfanyl group, and a C1-C6

alkylsulfonyl group, as in the general formulas (I) and

(II).

R is a hydrogen atom or a C1-C6 alkyl group, as in

the general formulas (I) and (II).

Rw is a hydrogen atom or P 2 , wherein P 2 represents,

as mentioned above, a protective group such as a t

butoxycarbonyl group (Boc).

[0193] In one embodiment, examples of the intermediate of

the present invention include compounds represented by

the following general formula (X-3-1) and salts thereof:

H N RW H CO 2 R 0 R2 (X-3-1)

R5 R3

R4

In the formula (X-3-1),

221102_G2572WO English Translation (Final) clean copy

R 2 is a hydrogen atom or a halogen atom,

R3 is a hydrogen atom, a halogen atom, a C1-C6 alkyl

group, a C1-C6 haloalkyl group, a C1-C6 alkoxy group, a

C1-C6 haloalkoxy group, a C3-Cs6 cycloalkyl group, a C3-Cs6

cycloalkoxy group, a heterocyclyl group, or a heteroaryl

group optionally substituted by a C1-C6 alkyl group,

R4 is a hydrogen atom, a halogen atom, a C1-C6 alkyl

group, a C1-C6 haloalkyl group, a C1-C6 alkoxy group, or a

C1-C6 haloalkoxy group,

R5 is a hydrogen atom, a halogen atom, a C1-C6 alkyl

group, a C1-C6 haloalkyl group, a C1-C6 alkoxy group, a

C1-C6 haloalkoxy group, or a heteroaryl group optionally

substituted by a C1-C6 alkyl group,

R 6 is a hydrogen atom or a halogen atom,

R is a hydrogen atom or a C1-C6 alkyl group, as in

the general formulas (I) and (II), and

Rw is a hydrogen atom or P 2 (wherein P 2 represents,

as mentioned above, a protective group such as a t

butoxycarbonyl group (Boc)).

[0194] In one embodiment, examples of the intermediate of

the present invention include compounds represented by

the following general formula (X-3-2) and salts thereof:

H RW -1N Rw N NCO 2 R 0 A1 (X-3-2)

221102_G2572WO English Translation (Final) clean copy

R is a hydrogen atom or a C1-C6 alkyl group, as in

the general formulas (I) and (II).

Rw is a hydrogen atom or P 2 (wherein P 2 represents,

as mentioned above, a protective group such as a t

butoxycarbonyl group (Boc)).

A' is a group selected from the group given below.

In the following formulas, * represents a binding

position.

C1 CF 3 Br CF 3 I CF3 CF 3 O CF 3 F CF3 F 3C CF 3

F CI F C

F3C N CF 3 CF 3 CF 3 CF 3 CF 3 CF3 NQ~> F

Cl CF3 Br Cl Cl Br Cl Br Br I Br Cl i F OMe

F __:tF F_[b C1 F Br F 2HCO CF 3 CI OCHF 2 Br OCHF 2 OCHF 2 OCHF 2 F

F 2HCO N F2 HCO OCHF 2 Cl OCF 3 Br OCF3 OCF 3 OCF 3 CF 3 F

OCF 3 OCHF 2 CHF 2 O Cl Br

N OCHF 2 CF3

[0195] In one embodiment, the intermediate of the present

invention may be a salt of the compound represented by

any of the formulas (X-1) to (X-3), the formula (X-1-1),

the formula (X-2-1), the formula (X-3-1) and the formula

221102_G2572WO English Translation (Final) clean copy

(X-2-3). Examples of the salt include, but are not

particularly limited to, the "acid-addition salt, etc."

and the "base-addition salt, etc." listed as examples of

the "pharmaceutically acceptable salt" mentioned above.

[0196] All references including publications, patent

applications and patents cited herein are incorporated

herein by reference in their entirety.

Examples

[0197] Hereinafter, the present invention will be

described in more detail with reference to Reference

Examples, Examples and Test Examples. However, the scope

of the present invention is not limited by these

examples. The names Reference Examples, Examples and

Test Examples are merely given for the sake of

convenience in order to discriminate among experimental

examples and do not mean that any of these examples are

not included in the present invention.

[0198] DUIS in the ionization mode of a mass spectrum is

a mixed mode of ESI and APCI.

[0199] In the present specification, 'H-NMR is indicated

by chemical shift (6) with tetramethylsilane as an

internal standard (0 ppm), and a coupling constant (J

value) is indicated by Hz unit, unless otherwise

specified. The abbreviation of the splitting pattern of

each peak means the following: s: singlet, d: doublet,

dd: double doublet, ddd: double double doublet, t:

221102_G2572WO English Translation (Final) clean copy

triplet, tt: triple triplet, quin: quintet, and m:

multiplet.

[0200] Abbreviations described in Reference Examples,

Examples, Test Examples and chemical structural formulas

are typically used in meanings that are generally used in

the field of organic chemistry or pharmaceuticals, and

specifically, should be understood as the abbreviations

of the following terms by those skilled in the art.

Me: methyl group

DMSO: dimethyl sulfoxide

tert: tertiary

N: normal

M: molar concentration

ESI: electrospray ionization

APCI: atmospheric pressure chemical ionization

EI: electronic ionization

CI: chemical ionization

[0201] Reference Example 1-(a)

Production of (R,E)-N-(3-chloro-5

(trifluoromethyl)benzylidene)-2-methylpropane-2

sulfinamide

N

CI F3

[0202] To a solution of 3.82 g of 3-chloro-5

(trifluoromethyl)benzaldehyde in toluene (20 ml), 2.35 g

221102_G2572WO English Translation (Final) clean copy

of (R)-2-methylpropane-2-sulfinamide (manufactured by

Combi-Blocks Inc.), 0.079 ml of pyrrolidine, and 4 g of a

molecular sieve (4 angstroms) were added at room

temperature under a stream of argon, and the mixture was

stirred at 700C for 2.5 hours.

After the completion of reaction, the reaction mixture

was filtered through celite and concentrated under

reduced pressure. Hexane was added to the concentration

residue, and the mixture was stirred at room temperature

for 30 minutes. A deposited solid was collected by

filtration, washed with hexane, and then dried under

reduced pressure at 600C to obtain 2.22 g of the title

compound as a white solid.

Mass spectrum (ESI, m/z): 312 [M+H]+.

[0203] Reference Example 2-(a), etc.:

Corresponding starting compounds were treated in the

same manner as in Reference Example 1-(a) to obtain

compounds described in the following Tables 1-1 to 1-8.

221102_G2572WO English Translation (Final) clean copy

[0204]

Table 1-1 Reference Structural formula Mass spectrum

example2-(a) (Cl, m/z): 356, 358 [M+H]+

Br, CF 3

Exaplen3-(a) (ESI, m/z): 404 [M+H]+

Example 4-(a) (DUIS,m/z):292[M+H]+

S CF 3

eape5-rc (ESI, m/z): 308 [M+H]+

CF 3

s O F, CF 3 Exaple)eFC (ESI, m/z): 296 [M+H]+

eame°ea)F (ESI, m/z): 346 [M+H]+

F-1 3 CF

221102_G2572WO English Translation (Final) clean copy

[ 02 0 5]

Table 1-2 Reference Example Structural formula Mass spectrum

Reference Example N (ESI, m/z): 296 [M+H]+ 9-(a) F

CF 3

Reference Example N c (ESI, m/z): 312 [M+H]+ 1O0-(a)I

CF 3

Reference Example N (ESI, m/z): 296 [M+H]+ 11-(a) F

F 3C

Reference Example F N (ESI, m/z): 312 [M+H]+ 12-(a) Exapl C

Reference Example ESI, m/z): 292 [M+H]+ 13-(a)

C;F, F

ReferenceExample N (ESI,mlz):292 [M+H] 14-(a) CF 3

221102_G2572WO English Translation (Final) clean copy

[0206]

Table 1-3 Reference Example Structural formula Mass spectrum

>S-1

Reference Example NESI, m/z): 330 [M+H]+. 15-(c) (EImz:30MH~ CI CF 3 F

Reference Example N (ESI, m/z): 318, 320 [M+H]+ 16-(a) Br OMe

Reference Example N DUIS, m/z): 278 [M+H]+ 17-(a)

CI CI

Reference Example N (ESI, m/z): 322, 324 [M+H]+ 18-(a)

Br CI

Reference Example NESI, m/z): 368 [M+H]+ 19-(a) r& Br BBr

>L..10 Reference Example N (ESI, m/z): 414, 416 [M+H]+ 20-(a)

1 Br

221102_G2572WO English Translation (Final) clean copy

[0207]

Table 1-4 Reference Example Structural formula Mass spectrum

Reference Example NESI, m/z): 370 [M+H]+ 21 -(c)

CI I

Reference Example N (ESI, m/z): 262 [M+H]+ 22-(a) CI F

Reference Example F (ESI, m/z): 306, 308 [M+H]+

23-(a) Br& F

Reference Example N ESI, m/z): 344 [M+H]+ F

F 0& F3 O 25(b C N" (ESI, mlz): 344[M+H]+ FF

Reference Example NE

F 0 OC F

Reference Example Brl 0 F N (ESI, m/z): 354, 356 [M+H]+ 26-(b) F

Br 0 F

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[ 02 0 8]

Table 1-5 Reference Example Structural formula Mass spectrum

Reference Example (ESI, m/z): 294 [M+H]+ 27-(b) F

O F

Reference Example N (ESI, m/z): 294 [M+H]+ 28-(b)F F

F 0

Reference Example (Cl, m/z): 342 [M+H+ 30-(c) F F F 0 0 F

Reference Example N (ESI, m/z): 328 [M+H]+ 31-(a)

CI OCF3

Reference Example NESI, m/z): 372, 374 [M+H+ 32-(a)

Br OCF 3

Reference Example NESI, m/z): 312 [M+H]+ 33-(a) F

F 3CO

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[ 02 0 9 ]

Table 1-6 Reference Example Structural formula Mass spectrum

Reference Example NESI, m/z): 312 [M+H]+. 34-(a) OCF 3 F

Reference Example N (ESI, m/z): 278 [M+H]+ 35-(a)

CF 3

Reference Example N (ESI, m/z): 294 [M+H]+ 36-(a) 6 OF OCF 3

Reference Example (ESI, m/z): 276 [M+H]+ 37-(a) F

0 F

Reference Example N (ESI, m/z): 260 [M+H]+ - F F

Reference Example N (ESI, mlz): 250 [M+H]+ 39-(a)N

221102_G2572WO English Translation (Final) clean copy

[0210]

Table 1-7 Reference Example Structural formula Mass spectrum

s~ Reference Example N (ESI, m/z): 266 [M+H]+ 40-(a)

0A

Reference Example NESI, m/z): 244 [M+H]+ 41 -(a)

CCI

Reference Example (ESI, m/z): 288, 290 [M+H]+ 42-(a)

BBr

Reference Example N (ESI, m/z): 276 [M+H]+ 43-(a) Ex eESI,m/z):2 N

[M+H]+

N Reference Example NEI /) 34[+] 44-(a) IEI lz:04M+]

s

Reference Example ESI, m/z): 295 [M+H]+ 45-(a) (E&

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[ 0 211]

Table 1-8 Reference Example Structural formula Mass spectrum

N Reference Example (ESI, m/z): 276 [M+H]+ 46-(a) O< F

F

Ns Reference Example (ESI, m/z): 278 [M+H]+ 47-(a)I

CF 3

[0212] Reference Example 1-(b)

Production of methyl (S)-3-(((R)-tert

butylsulfinyl)amino)-3-(3-chloro-5

(trifluoromethyl)phenyl)propanoate

1 0

C1 CFj

[0213] To 33.3 g of zinc, 5.05 g of copper(I) chloride

was added with stirring under a stream of argon, followed

by deaeration under reduced pressure at a bath

temperature of 70°C for 15 minutes. After purging with

argon, 45 ml of tetrahydrofuran was added thereto under a

stream of argon, and the mixture was stirred at 700C for

1 hour. Then, the bath temperature was lowered to 40°C,

and 10.4 ml of methyl bromoacetate was added dropwise

221102_G2572WO English Translation (Final) clean copy

thereto at an internal temperature of 300C to 370C. After

the completion of addition, the mixture was stirred at a

bath temperature of 50°C for 1 hour. The reaction

mixture was brought back to room temperature and then

cooled in an ice salt bath. A solution of 5.00 g of

(R,E)-N-(3-chloro-5-(trifluoromethyl)benzylidene)-2

methylpropane-2-sulfinamide synthesized in the same

manner as in Reference Example 1-(a) in tetrahydrofuran

(22.5 ml) was added dropwise thereto at an internal

temperature of -5°C or lower under a stream of argon, and

the mixture was further washed repeatedly with 7.50 ml of

tetrahydrofuran. After the completion of dropwise

addition, the mixture was cooled in an ice bath and

stirred for 2 hours.

After the completion of reaction, the reaction

mixture was filtered through celite (545) and washed with

ethyl acetate. Then, a saturated aqueous solution of

ammonium chloride was added to the filtrate, and the

mixture was stirred. This mixed solution was filtered,

and the filtrate was separated into organic and aqueous

layers. The organic layer was washed with saturated

saline, dried over anhydrous magnesium sulfate, filtered,

and concentrated under reduced pressure. The obtained

concentration residue was purified by medium-pressure

preparative chromatography (silica gel, eluting solvent:

hexane:ethyl acetate) to obtain 4.82 g of the title

compound as a pale yellow oil.

221102_G2572WO English Translation (Final) clean copy

Mass spectrum (ESI, m/z): 386 [M+H]+.

[0214] Reference Example 2-(b), etc.:

Corresponding starting compounds were treated in the

same manner as in Reference Example 1-(b) to obtain

compounds described in the following Tables 2-1 to 2-8.

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[ 0 215]

Table 2-1 Reference Structural formula Mass spectrum

Reference HN O (Cl, m/z): 430, 432 [M+H]+ Example 2-(b)0 1 Br CF 3

>L%.0 Reference HN O (ESI, m/z): 478 [M+H]+ Example 3-(b)0 1 1 CF 3

> s1 Reference HN 4b (ESI, m/z): 366 [M+H]+ Example 4-(b)0

CF 3

> s1 Reference HN (ESI, m/z): 382 [M+H]+ Example 5-(b)0 1 O CF 3

Reference HN O (ESI, m/z): 370 [M+H]+ Example 6-(b) ½ F CF 3

R efnce HN (ESI, m/z): 420 [M+H]+ Example 7-(b)½

F 3C CF 3

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[ 0 216]

Table 2-2 Reference Example Structural formula Mass spectrum

Reference Example HN CO 2 Me (ESI, m/z): 370 [M+H]+ 9-(b) F

CF 3

Reference Example HN CC 2 Me (ESI, m/z): 386 [M+H]+ 1 0-(b)N

CF 3

Reference Example HN CO 2 Me (ESI, m/z): 370 [M+H]+

F 3C

Reference Example HN CO2MO (ESI, m/z): 386 [M+H]+ 12-(b) CM

F 3C

Reference Example H(ESI, m/z): 370 [M+H]+ 13-(b)CF CF3 F

Reference Example HN O (ESI, m/z): 366 [M+H]+ 14-(b) (

AFCF 3

221102_G2572WO English Translation (Final) clean copy

[0217]

Table 2-3 Reference Example Structural formula Mass spectrum

>KO Reference Example HN O (ESI, m/z): 404 [M+H]+ 15-(d) 0 CI CF 3 F

Reference Example HN CO 2 Me (ESI, m/z): 392, 394 [M+H]+ 16-(b) Br: OMe

Reference Example HN 0 (ESI, m/z): 352 [M+H]+ 17-(b)0

CI C

Reference Example HN O (ESI, m/z): 396, 398 [M+H]+ 18-(b)

Br CI

Reference Example HO (ESI,mz):442[M+H]+ 19-(b)

Br Br

Reference Example HN OMe (ESI,m/z):488,490[M+H] 20-(b)0

I Br

221102_G2572WO English Translation (Final) clean copy

[ 0 218 ]

Table 2-4 Reference Example Structural formula Mass spectrum

Reference Example HN (ESI, m/z): 444 [M+H]+ 21 -(d)0

CI I

Reference Example HN CQ 2Me (ESI, m/z): 336 [M+H]+ 22-(b)F

Cl

Reference Example H CO2Me (ESI, m/z): 380, 382 [M+H]+ 23-(b) COMFEImz:8,8[+]

Br

Reference Example HN 0¾ (ESI, m/z): 418 [M+H]+ 24-(c) F F 0 CF 3

Reference Example HN o ESI, m/z): 384 [M+H]+ 25-(c) H F

C1 O1j F

Reference Example HN (ESI, m/z): 428,430 [M+H]+ 26-(c) 0 F 1 Br O F

221102_G2572WO English Translation (Final) clean copy

[ 0 219 ]

Table 2-5 Reference Example Structural formula Mass spectrum

Reference Example HN (ESI, m/z): 368 [M+H]+ 27-(c) I . F O F

> S',

Reference Example HN O (ESI, m/z): 46 [M+H]+ 28-(c) FOM EImz:6[+] F F

Reference Example HN (ESI, m/z): 416 [M+H]+ 30-(d) F

F 0 0 F CI CF

Reference Example HN CO2M (ESI, m/z): 402 [M+H]+ 31-(b) 0

CO 00F 3

sz Reference-Example HN (ESI,mz):446,448[M+H] 32-(b) 0

Br 00F 3

>0s Reference Example HN CO 2Me (ESI, m/z): 386 [M+H]+ 33-(b) F

221102_G2572WO English Translation (Final) clean copy

[0220]

Table 2-6 Reference Example Structural formula Mass spectrum

Reference Example HN O (ESI, m/z): 386 [M+H]+ 34-(b) E

OCF 3 F

Reference Example HN (ESI, m/z): 352 [M+H]+ 35-(b) 0

CF 3

Reference Example HN CO 2Ms (ESI, m/z): 368 [M+H]+ 36-(b)

OCF 3

Reference Example HN CO 2Me (ESI, m/z): 350 [M+H]+ 37-(b) F

0F

Reference Example H O (ESI, m/z): 334 [M+H]+ 38-(b) F F

Reference Example HN 01 (ESI, m/z): 324 [M+H]+ 39-(b) (

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[ 0 2 21]

Table 2-7 Reference Example Structural formula Mass spectrum

Reference Example HN O (ESI, m/z): 340 [M+H]+ 40-(b) O

Reference Example HN (E0mz:1[+]

Cl

Reference Example HN (ESI,m/z):362,364[M+H]+ 42-(b)

Br

Reference Example HN (ESI, m/z): 350 [M+H]+ 43-(b) 0 N

Reference Example HN (ESI, m/z): 378 [M+H]+ 44-(b) MIENml)38[+]

Reference Example HN (ESI, m/z): 369 [M+H]+ 45-(b) 0(EImz36[+] N 0

221102_G2572WO English Translation (Final) clean copy

[0222]

Table 2-8 Reference Example Structural formula Mass spectrum

HN_,

, Reference Example O (ESI, m/z): 350 [M+H]+ 46-(b) (EImz35[+]

F

Reference Example HN o (ESI, m/z): 352 [M+H]+ 47-(b) 0(EImz35[+]

CF 3

[0223] Reference Example 1-(c)

Production of methyl (S)-3-amino-3-(3-chloro-5

(trifluoromethyl)phenyl)propanoate hydrochloride

HCI H 2N Os

Ci CFa

[0224] To a solution of 24.6 g of methyl (S)-3-(((R)

tert-butylsulfinyl)amino)-3-(3-chloro-5

(trifluoromethyl)phenyl)propanoate synthesized in the

same manner as in Reference Example 1-(b) in cyclopentyl

methyl ether (270 ml), 2.52 ml of methanol and 34.2 ml of

a 4 M solution of hydrogen chloride in cyclopentyl methyl

ether were added at room temperature under a stream of

argon, and the mixture was stirred at room temperature

for 1 hour.

221102_G2572WO English Translation (Final) clean copy

After the completion of reaction, the reaction

mixture was concentrated under reduced pressure. 50 ml

of cyclopentyl methyl ether and 600 ml of hexane were

added to the concentration residue, and the mixture was

stirred at room temperature for 1 hour. A deposited

solid was collected by filtration, washed with hexane,

and then dried under reduced pressure at 500C to obtain

17.5 g of the title compound as a white solid.

Mass spectrum (ESI, m/z): 282 [M+H]+.

[0225] Reference Example 2-(c), etc.:

Corresponding starting compounds were treated in the

same manner as in Reference Example 1-(c) to obtain

compounds described in the following Tables 3-1 to 3-7.

221102_G2572WO English Translation (Final) clean copy

[0226]

Table 3-1 Reference Structural formula Mass spectrum Example HCI

Exampe2-(c) H (Cl, m/z): 326, 328 [M+H]+

Br CF 3

HCI

xarpe3-(c) H2N O (ESI, m/z): 374 [M+H]+

1 CF 3 HCI

Exarple 4-(c) H O1 (DUIS, m/z): 262 [M+H]+

CF 3

HCI

Reference H 2N 02 Example 5-(c) (ESI,mlz):278[M+H]+

O CF3

HCI

exaple6-(c) H2N O (ESI, m/z): 266 [M+H]+

F CF 3

HCI

Reference H 2N CO 2 Me (ESI, m/z): 266 [M+H]+ Example 9-(c) IF(EImz26[H] CF 3

221102_G2572WO English Translation (Final) clean copy

[0227]

Table 3-2 Reference Example Structural formula Mass spectrum HCI

Reference Example H2N CO 2 Me (ESI, m/z): 282 [M+H]+ 10-(c) Cl I1~i CF 3

HCI

Reference Example H 2N CO 2Me (ESI, m/z): 266 [M+H]+ 11-(c) F

F 3C

HCI

Reference Example H 2N CO 2Me (ESI, m/z): 282 [M+H]+ 12-(c) Cl(EImz28M+]

F 3C HCI H 2N Reference Example O 13-(c) 13-c)(ESI, mlz): 266 [M+H+ CF 3 F

HCI H 2N Os Reference Example 0 ESI, m/z): 300 [M+H]+ 15-(e) E CI CF 3 F

HCI H 2N CO 2Me Reference Example ESI, m/z): 288,290 [M+H]+ 16-(c) Br OMe

221102_G2572WO English Translation (Final) clean copy

[ 02 2 8]

Table 3-3 Reference Example Structural formula Mass spectrum

HCI

Reference Example H2N 01 (DUIS, m/z): 248 [M+H]+ 17-(c)

( Cl Cl

HCI

Reference Example H 2N 0 (ESI, m/z): 338 [M+H]+ 19-(c) ( Br Br

HCI

Reference Example H2N OMe (ESI, m/z): 384, 386 [M+H]+ 20-(c) (E0mz:8,8[+]

1Br

HCI

Reference Example H 2N Os (ESI, m/z): 340 [M+H]+ 21-(e) (

CI I HCI

Reference Example H2N CO 2Me (ESI, m/z): 232 [M+H]+ 22-(c) N.F

Cl

Reference Example H 2N CO 2 Me 23-(c) I. F (ESI, mlz): 276,278 [M+H+

BrT

221102_G2572WO English Translation (Final) clean copy

[ 02 2 9 ]

Table 3-4 Reference Example Structural formula Mass spectrum

HCI

Reference Example H2N 0 (ESI, m/z): 314 [M+H]+ 24-(d) F

( F O CF 3

HCI

Reference Example H2N (ESI, m/z): 280 [M+H+ 25-(d) F (ESI,mlz): 2 [M+H]

Cl 0 F

HCI

Reference Example H2N ESI, m/z): 26 [M+H+ 26-(d) F ( Br 0 F HCI H 2N O F 011 Reference Example H (ESI, m/z): 32 [M+H]+ 27-(d) F F F F

Reference Example HN CO 2Me (ESI, mlz): 264 [M+H]+ 28-(d) F< F

HOP F O, O0 Reference Example H2N 0w (ESI, mlz): 312 [M+H+ 30-(e) F N

FA 0 F

221102_G2572WO English Translation (Final) clean copy

[0230]

Table 3-5 Reference Example Structural formula Mass spectrum HCI H 2N O Reference Example O (ESI, m/z): 298 [M+H]+ 31 -(c) 0EImz:9[+]

CI OCF 3

HCI

Reference Example H 2N (ESI, m/z): 342,344 [M+H]+ 32-(c) (E0mz:4,4[+]

Br OCF 3

Reference Example H 2N CO2 Me ESI, m/z): 282 [M+H]+ 33-(c) F(EImz28[+]

F 3CO

HCI

Reference Example H 2N Os (ESI, m/z): 248 [M+H]+ 35-(c) 0(EImz24[+]

CF 3 HCI

Reference Example H 2N CO 2Me (ESI, m/z): 264 [M+H]+ 36-(c) OCF 3

H CI

Reference Example C0 2 Me (ESI, m/z): 246 [M+H+ 37-(c) F 0 F

221102_G2572WO English Translation (Final) clean copy

[ 0 2 31]

Table 3-6 Reference Example Structural formula Mass spectrum

HCI

Reference Example H2N 0 (ESI, m/z): 220 [M+H]+ 38-(c) E (ESI,m/z):230[M+H]+

0 F F

HCI

Reference Example H 2N E m 2[

39-(c) 0 (ESI,mlz):220[M+H]+

HCI

Reference Example H2 NESI, m/z): 2 [M+H+ 40-(c) E

HCI H2N O Reference Example o ESI, m/z): 26 [M+H]+ 43-(c) (

HCI H 2N 0 Reference Example 0 (ESI, mlz): 274 [M+H]+ 44-(c) N

HOI H 2N 0 Reference Example 0(Smz:25[+l 45-(c)(EImz26[+] N O

221102_G2572WO English Translation (Final) clean copy

[0232]

Table 3-7 Reference Example Structural formula Mass spectrum HCI

H2 N O

Reference Example o (ESI, m/z): 246 [M+H]+ 46-(c) 0 F F

HCI

Reference Example 0 ESI, m/z): 248 [M+H]+ 47-(c)(EImz24[+]

CF 3

[0233] Reference Example 1-(d)

Production of methyl (S)-3-(2-((tert

butoxycarbonyl)amino)acetamido)-3-(3-chloro-5

(trifluoromethyl)phenyl)propanoate

0 0

Cl 'CF2

[0234] To a solution of 2.23 g of methyl (S)-3-amino-3

(3-chloro-5-(trifluoromethyl)phenyl)propanoate

hydrochloride synthesized in Reference Example 1-(c), and

0.977 ml of triethylamine in dichloromethane (20 ml),

1.36 g of (tert-butoxycarbonyl)glycine and 1.61 g of 1

(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride

were added at room temperature under a stream of argon,

221102_G2572WO English Translation (Final) clean copy

and the mixture was stirred at room temperature for 30

minutes.

After the completion of reaction, a saturated

aqueous solution of ammonium chloride was added to the

reaction mixture, and the mixed solution was subjected to

extraction with dichloromethane. The organic layer was

washed with saturated saline, dried over anhydrous sodium

sulfate, filtered, and concentrated under reduced

pressure. The concentration residue was purified by

medium-pressure preparative chromatography (silica gel,

eluting solvent: hexane:ethyl acetate) to obtain 2.92 g

of the title compound as a colorless oil.

Mass spectrum (ESI, m/z): 439 [M+H]+.

[0235] Reference Example 2-(d), etc.:

Corresponding starting compounds were treated in the

same manner as in Reference Example 1-(d) to obtain

compounds described in the following Tables 4-1 to 4-8.

221102_G2572WO English Translation (Final) clean copy

[ 02 3 6]

Table 4-1 Reference Structural formula Mass spectrum

0

Reference 0 N N Example 2-(d) H 0 (Cmz):483,485[M+H]+

Br CF 3

0 H Reference O N O ( m 5[ Example 3-(d) H 0 (ESI,mlz):531[M+H]

CF 3

0 H Reference O N m 4[+ Example 4-(d) H 0 (ESI,mlz):419[M+H

CF 3

0H Reference o ^N 04 E,/N M Example 5-(d) H o (ESI,mlz):435[M+H]

0 CF3

H Reference 0 1 N 'YN OJ 0>1 Example 6-(d) H 0 0 (ESI, m/z): 423 [M+H]+

F CF 3

H 1 Reference 0' N -- N r0M Example 7-(d) H 0 (ESI, mlz): 473 [M+H]+

F 3C CF 3

221102_G2572WO English Translation (Final) clean copy

[0237]

Table 4-2 Reference Example Structural formula Mass spectrum

Reference Example 0 N C02Me (ESI, m/z): 445 [M+Na]+ 9-(d) H 0 F

CF 3

Reference Example 0 N CO2Me 10-(d) H C ( mz):461[M+Na]

CF 3

Reference Example 0 N CO 2 Me (ESI, m/z): 445 [M+Na]+ 11-(d) 0 F

F 3C

Reference Example o N CO 2Ms (ESI, m/z): 461 [M+Na]+ 12-(d) H Nc

F 3C

0 H 0 N Reference Example H 0 (ESI,mlz):423[M+H]+ 13-(d) CF 3 F

0 H0 0 N N ON Reference Example H 14-(d) 0 0 (ESI, m/z): 419 [M+H]+

CF 3

221102_G2572WO English Translation (Final) clean copy

[ 02 3 8]

Table 4-3 Reference Example Structural formula Mass spectrum

O N N O Reference Example H 0 0 (ESI, m/z): 457 [M+H]+ 15-(f) CI CF3 F

O N Reference Example H ESI,mlz):445,447[M+H]+ 16-(d)0 0 EI /)44,47[Hj BrN OMe

Reference Example ON Om 7 17-(d) H (ESI, m/z): 427 [M+Na]+

C Cl

J H Reference Example 04 DUS m/z):N M 18-(d) H 0 0 (ESI, mlz): 449, 451 [M+H+

Br Cl

0 H

Referenc Example > OAN' N 0 (DUIS, mlz): 493 [M-H]

Br Br

Reference Example AN N 0- (ESI, m/z): 541, 543 [M+H]+ 20-(d) H 0

Br '

221102_G2572WO English Translation (Final) clean copy

[ 02 39]

Table 4-4 Reference Example Structural formula Mass spectrum

Reference Example o NI (ESI m 47MH 21-(f) H o (ESI,mlz):497[M+H]

CI I

Reference Example O N CO 2 Me (ESI, m/z): 389 [M+H]+ 22-(d) H oF

Cl

ReferenceExample Q N CO7Me (ESI, m/z): 433, 435 [M+H]+

Br

_J H Reference Example No N m 41MH Re H (ESI, m/z): 471 [M+H]+

F J-0 CF:3

25-(e) F 0 F 0 Reference Example : 0 NJ ClOF HN 1 25-e)H F (ESI, mlz): 437 [M+H]+

Ci 0 ',F

Reference Example N- ESI, mz): 481,483[M+H]+ 26-(e) H 0 F

Br 0 F

221102_G2572WO English Translation (Final) clean copy

[0240]

Table 4-5 Reference Example Structural formula Mass spectrum

0 N Reference Example H N 0 ESI, m/z): 421 [M+H]+ 27-(e) F

F F

Reference Example 0 NCOMe (ESI,mlz):421[M+H]+ 28-(e) H 0 F

F 0 Refeenc Example ESI, m/z): 469 [M+H]+

Reference Example 0 ESI /) N4 Reference Examp (ESI, m/z): 469 [M+H]+

F 1 NOF

0 H Reference Example o0 cN (ESNm 31-(d) 32-(d) HF (ESI,mlz):455[M+H]+

CO OCF 3

Reference Example Oj-1N 04 N 32-(d) H 0 0 (ESI, mlz): 499, 501 [M+H]+

Br 0CF 3

0 H )NO AlN-, N 0 e Reference Example H 0 N CO 2 E Smz:49[H] 33-(d)F(EImz43[ H] F 3C0

221102_G2572WO English Translation (Final) clean copy

[0241]

Table 4-6 Reference Example Structural formula Mass spectrum

ON 5H 0 N Reference Example H 0 O (ESI,mlz):439[M+H]+ 34-(d) 0(Smz:49[+] OCF3 F

Reference Example ONESI, m 405 [M+H]+ 35-(d) H 0 (ESI, m/z): 405 [M+H]+

CF 3

F ( m 4 M Reference Example 36-(d) H F (ESI, m/z): 443 [M+Na]+

QCF 3

0 H Reference Example (ESI, m/z): 403 [M+H]+

0 149 F

O0 N N ,

Reference Example H 0 0 (ESI, mlz): 409 [M+Na]+ 38-(d)I

F

ON H Reference Example H 0 0 (ESI, mlz): 377 [M+H]+ 39-(d)

221102_G2572WO English Translation (Final) clean copy

[0242]

Table 4-7 Reference Example Structural formula Mass spectrum

Reference Example O K N O ESI, mlz):393 [M+H]+

Reference Example Q N ESI, mlz): 371 [M+H]+ 43-(d) H

ON Reference Example H- N (ESI, m/z): 403 [M+H]+

ReferenceExample N N Br Reerc EH (ESI, m/z): 431 [M+H]+

44 -(d)00

O N Reference Example H 0 0 (ESI, m/z): 43 [M+H]+ 45-(d) N

>O S1 0 N Reference Example H 0(Smz:42[+] N 45-(d)(EImz42[ H]

0

221102_G2572WO English Translation (Final) clean copy

[0243]

Table 4-8 Reference Example Structural formula Mass spectrum

Reference Example ( 0ESI, m/z): 425 [M+Na]+

O ,V N -XN 0 F O0

46-(d) EI /)42 M N]

Reference Example H 0o(ESI,m/z):427[M+Na]+

CF3

[0244] Reference Example l-(e)

Production of methyl (S)-3-(2-aminoacetamido)-3-(3

chloro-5-(trifluoromethyl)phenyl)propanoate hydrochloride

HCI

H 2N 0 0

CI CF 3

[0245] To a solution of 27.8 g of methyl (S)-3-(2-((tert

butoxycarbonyl)amino)acetamido)-3-(3-chloro-5

(trifluoromethyl)phenyl)propanoate synthesized in the

same manner as in Reference Example 1-(d) in cyclopentyl

methyl ether (190 ml), 60 ml of a 4 M solution of

hydrogen chloride in cyclopentyl methyl ether was added

at room temperature under a stream of argon, and the

mixture was stirred at room temperature for 7 hours.

221102_G2572WO English Translation (Final) clean copy

After the completion of reaction, the reaction

mixture was concentrated under reduced pressure to obtain

21.5 g of the title compound as a pale yellow oil.

Mass spectrum (ESI, m/z): 339 [M+H]+.

[0246] Reference Example 2-(e), etc.:

Corresponding starting compounds were treated in the

same manner as in Reference Example 1-(e) to obtain

compounds described in the following Tables 5-1 to 5-8.

221102_G2572WO English Translation (Final) clean copy

[0247]

Table 5-1 Reference Structural formula Mass spectrum

HCI H Reference H 2N (Cl, m/z): 383, 385 [M+H]+ Example 2-(e) 0

Br CF 3

HCI H

Reference H 2N N Os (ESI, m/z): 431 [M+H]+ Example 3-(e) 0 0

11 CF 3

HCI H N 1 Reference H 2N N OT Example 4-(e) 0 0 (ESI, m/z): 319 [M+H]+

CF 3

HCI H Reference H 2N N O S Example 5-(e) O 0 (ESI,mz):335[M+H]+

0 CF 3

HCI H Reference H 2N N O (ESI, m/z): 323 [M+H]+ Example 6-(e) 0 o

F CF3

HCI H

Reference H 2N N Os Example 7-(e) a0 (ESI, m/z): 373 [M+H]+ F 3C CF 3

221102_G2572WO English Translation (Final) clean copy

[0248]

Table 5-2 Reference Example Structural formula Mass spectrum HCI H H2 N N 0s R rence Example (ESI, m/z): 371 [M+H]+

F 3C N

HCI H Reference Example H 2N N CO 2Me (ESI, m/z): 323 [M+H]+ 9-(e) 0 F(EImz32[H] CF 3

HCI H Reference Example H 2N N 2Me (ESI, m/z): 339 [M+H]+ 1O0-(e) 0 Cl (EImz39[H]

CF 3

HCI H Reference Example H2N N CO 2Me (ESI, m/z): 323 [M+H]+ 1-(e) 0 F(EImz32[H]

HCI H Reference Example H 2N ESI, m/z): 33 [M+H]+ 12-(e) 0 Cl (EImz39[H]

F 3 CN

HCI H 0 (ES--mlz):323[M+H] Reference Example 13-(e) N

CF 3 F

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[0249]

Table 5-3 Reference Example Structural formula Mass spectrum HCI H H2N N O Reference Example (0 ESI, m/z): 357 [M+H]+ 15-(g)I CI CF 3 F HCI H H 2N N O Reference Example 0 0 (ESI, m/z): 345, 347 [M+H]+ 16-(e) Br OMe

HCI H Reference Example H 2N (ESI, m/z): 305 [M+H]+ 17-(e) ( 3

CI Cl

HCI H Reference Example H2N N O N(ESI, m/z): 349,351 [M+H]+ 18-(e) 0 0 EImz:4,5[+]

Br Cl

HCI H Reference Example H 2N (ESI, m/z): 395 [M+H]+ 19-(e) O O

Br Br

HCI H Reference Example H 2N N (ESI, m/z): 441, 443 [M+H]+ 20-(e) O O

Br I

221102_G2572WO English Translation (Final) clean copy

[0250]

Table 5-4 Reference Example Structural formula Mass spectrum

HCI H Reference Example H 2N N (ESI, m/z): 397 [M+H]+ 21-(g) 0 P

CI I

HCI H Reference Example H2N N CO 2 Me (ESI, m/z): 289 [M+H]+ 22-(e) 0 F

CI

HCI H Reference Example H 2N N CO 2 Me (ESI, m/z): 333, 335 [M+H]+ 23-(e) 0 F(EImz33,5M+f

Br

HCI H Reference Example H 2N (ESI, m/z): 371 [M+H]+ 24-(f) F 0 O

F 0 CF 3

HCI H Reference Example H2N N CO1 (ESI, m/z): 337 [M+H]+ 25-(f) 0 F (EImz37[ H] Cl 0 'jF

HCI H Reference Example H2N CO 2 Me (ESI, m/z): 381, 383 [M+H]+ 26-(f) 0 F

Br 0 F

221102_G2572WO English Translation (Final) clean copy

[ 0 2 51]

Table 5-5 Reference Example Structural formula Mass spectrum HCI H H2 N N CO 2 Me Reference Example O F (ESI, m/z): 321 [M+H]+ 27-(f) F

F

HCI H Reference Example H 2N N CO 2 Me (ESI, m/z): 321 [M+H]+ 28-(f) IF 0 . F(EImz32MH]

F 0 HCI H H2 N N CO 2 Me Reference Example 0 29-(b) F (ESI, m/z): 369 [M+H]+ F 0 N N

HCI H Reference Example H2N N Os (ESI, m/z): 369 [M+H]+ 30-(g) F O O F

F 0 O F

HCI H Reference Example H 2N N 0s (ESI, m/z): 355 [M+H]+ 31 -(e) 0 0 ' '

CI OCF 3

HCI H Reference Example H 2N N 0 N (ESI, m/z): 399,401 [M+H]+ 32-(e) 0 0

Br OCF 3

221102_G2572WO English Translation (Final) clean copy

[0252]

Table 5-6 Reference Example Structural formula Mass spectrum

HCI H

Reference Example H2N N CO 2 Me 33-(e) 0 F (ESI, m/z): 339 [M+H]+

F 3CO

HCI H H 2N N 0s Reference Example (O ESI, m/z): 339 [M+H]+ 34-(e)I OCF 3 F

HCI H Reference Example H 2N N Os (ESI, m/z): 305 [M+H]+ 35-(e) (E0ml)35[0]

CF 3

HCI H Reference Example H2N (ESI, m/z): 321 [M+H]+ 36-(e) 0 0

OCF 3

HCI H Reference Example H2 N N Os (ESI, m/z): 303 [M+H]+ 37-(e) O O F

0 F HCI H H 2N N Os Reference Example 0 0 (ESI, m/z): 287 [M+H]+ 38-(e) - 15 F

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[ 02 5 3]

Table 5-7 Reference Example Structural formula Mass spectrum HCI H

Reference Example H2N NS ) [ 39-(e) 0 6 0 (ESI, mlz): 277 [M+H]+

HCI H Reference Example H 2N N (ESI, m/z): 293 [M+H]+ 40-(e) ( 2 1 0

HCI H Reference Example H 2N N O (ESI, m/z): 271 [M+H]+ 41 -(e) (E0ml)210+]

CI

HCI H Reference Example H 2N N O (ESI, m/z): 315, 317 [M+H]+ 42-(e) 0 (E0mz:1,1[+]

Br

HCI H H-2N -- yN O Reerne xap ReferenceExample 0 0 (ESI, m/z): 303 [M+H]+ 43-(e) N'N

HCI H H 2N N O Reference Example 0 0 (ESI, m/z): 331 [M+H]+ 44-(e) -N

221102_G2572WO English Translation (Final) clean copy

[0254]

Table 5-8 Reference Example Structural formula Mass spectrum HCI H H2N N Reference Example 0 0 (ESI, m/z): 322 [M+H]+ 45-(e) N 0 HCI H H2N N O Reference Example (ESI, m/z): 303 [M+H]+ 46-(e) 0 F F

HCI H H2 N O ¾N Reference Example 0 0 (ESI, m/z): 305 [M+H]+ 47-(e)I

CF 3

[0255] Reference Example 18-(c)

Production of methyl (S)-3-amino-3-(3-bromo-5

chlorophenyl)propanoate hydrochloride

HCI H 2N 0

Br C

[0256] To a solution of 2.26 g of methyl (S)-3-(3-bromo

-chlorophenyl)-3-(((R)-tert

butylsulfinyl)amino)propanoate synthesized in Reference

Example 18-(b) in 1,4-dioxane (20 ml), 0.23 ml of

methanol and 4.1 ml of a 4 M solution of hydrogen

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chloride in 1,4-dioxane were added at room temperature

under a stream of argon, and the mixture was stirred at

room temperature for 18 hours.

After the completion of reaction, 60 ml of hexane

was added to the reaction mixture, and the mixture was

stirred at room temperature for 1 hour. The reaction

mixture was concentrated under reduced pressure. 10 ml

of tert-butyl methyl ether was added to the concentration

residue, and the mixture was stirred at room temperature

for 3 hours. A solid was collected by filtration and

dried under reduced pressure to obtain 1.07 g of the

title compound as a white solid.

Mass spectrum (ESI, m/z): 292, 294 [M+H]+.

[0257] Reference Example 7-(c), etc.:

Corresponding starting compounds were treated in the

same manner as in Reference Example 18-(c) to obtain

compounds described in the following Table 6.

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[ 02 5 8]

Table 6 Reference Example Structural formula Mass spectrum

HCI

Reference Example H 2N Os 7-(c)

F3 C CF 3

HCI

H2 N 0 ReferenceExample 14-(c) (ESI, m/z): 262 [M+H+

CF 3

HCI H2N O0 Reference Example 34-(c) 0 OCF 3 F

HCI

Reference Example H2N 0 (ESI, m/z): 214 [M+H]+ 41-(c) (

CI HCI

Reference Example H 2N 0s (ESI, m/z): 258, 260 [M+H]+ 42-(c) (E0mz:5,6[+] Br

[0259] Reference Example 8-(a)

Production of methyl (S)-3-(3-(lH-pyrazol-1-yl)-5

(trifluoromethyl)phenyl)-3-(2-((tert

butoxycarbonyl)amino)acetamido)propanoate

221102_G2572WO English Translation (Final) clean copy

J, HY 0 Fa 0

F 3C N -N

[0260] To a solution of 300 mg of methyl (S)-3-(2-((tert

butoxycarbonyl)amino)acetamido)-3-(3-bromo-5

(trifluoromethyl)phenyl)propanoate synthesized in the

same manner as in Reference Example 2-(d) in N,N

dimethylformamide (3 ml), 51 mg of pyrazole, 392 il of

trans-N,N'-dimethylcyclohexane-1,2-diamine, and 345 mg of

potassium carbonate were added at room temperature under

a stream of argon, and the mixture was stirred at room

temperature for 10 minutes under argon bubbling.

Subsequently, 236 mg of copper(I) iodide was added

thereto at room temperature, and the mixture was stirred

at 900C for 3 hours.

After the completion of reaction, water was added to

the reaction mixture, and the mixed solution was

subjected to extraction with ethyl acetate. The organic

layer was washed with a saturated aqueous solution of

ammonium chloride and saturated saline, dried over

anhydrous magnesium sulfate, filtered, and concentrated

under reduced pressure. The obtained residue was

purified by medium-pressure preparative chromatography

(silica gel, eluting solvent: hexane:ethyl acetate) to

obtain 81 mg of the title compound as a colorless oil.

Mass spectrum (ESI, m/z): 471 [M+H]+.

221102_G2572WO English Translation (Final) clean copy

[0261] Reference Example 29-(a):

A corresponding starting compound was treated in the

same manner as in Reference Example 8-(a) to obtain a

compound described in the following Table 7.

[0262]

Table 7 Reference Example Structural formula Mass spectrum

Reference Example N (ESI, m/z): 469 [M+H]+ 29-(a) F

[0263] Reference Example 14-(e)

Production of methyl (S)-3-(2-aminoacetamido)-3-(4

methyl-3-(trifluoromethyl)phenyl)propanoate hydrochloride

Hc H

0 0

CF

[0264] To 293 mg of methyl (S)-3-(2-((tert

butoxycarbonyl)amino)acetamido)-3-(4-methyl-3

(trifluoromethyl)phenyl)propanoate synthesized in

Reference Example 14-(d), 3.2 ml of tert-butyl methyl

ether and 0.657 ml of a 4 M solution of hydrogen chloride

in 1,4-dioxane were added in a nitrogen atmosphere, and

the mixture was stirred at room temperature for 3 hours.

0.657 ml of a 4 M solution of hydrogen chloride in 1,4

dioxane was further added thereto, and the mixture was

221102_G2572WO English Translation (Final) clean copy

stirred at room temperature for 3 hours. 0.657 ml of a 4

M solution of hydrogen chloride in 1,4-dioxane was

further added thereto, and the mixture was stirred at

room temperature for 2 hours. After the completion of

reaction, the reaction mixture was concentrated under

reduced pressure to obtain 259 mg of the title compound.

Mass spectrum (ESI, m/z): 319 [M+H]+.

[0265] Reference Example 15-(a)

Production of (3-chloro-4-fluoro-5

(trifluoromethyl)phenyl)methanol

CI' ' CF

[0266] To a solution of 1.00 g of 3-chloro-4-fluoro-5

(trifluoromethyl)benzoic acid in tetrahydrofuran (20 ml),

9.16 ml of a 0.9 M solution of a borane-tetrahydrofuran

complex in tetrahydrofuran was added in an ice bath under

a stream of argon, and the mixture was stirred at room

temperature for 20 hours.

After the completion of reaction, 2 M hydrochloric

acid was added to the reaction mixture, and the mixed

solution was subjected to extraction with ethyl acetate.

The organic layer was washed with a saturated aqueous

solution of sodium bicarbonate, dried over anhydrous

magnesium sulfate, filtered, and concentrated under

reduced pressure. The obtained residue was purified by

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medium-pressure preparative chromatography (silica gel,

eluting solvent: hexane:ethyl acetate) to obtain 1.06 g

of the title compound as a colorless oil.

Mass spectrum (EI, m/z): 228 [M]+.

[0267] Reference Example 21-(a), etc.:

Corresponding starting compounds were treated in the

same manner as in Reference Example 15-(a) to obtain

compounds described in the following Table 8.

[0268]

Table 8 Reference Example Structural formula Mass spectrum

HO Reference Example CEl, m/z): 268 [M]+ 21 -(a) I

HO Reference Example El, m/z): 240 [M]+ 30-(a) F F F O 0 F

[0269] Reference Example 21-(b)

Production of 3-chloro-5-iodobenzaldehyde

Os

[0270] To a solution of 2.04 g of (3-chloro-5

iodophenyl)methanol synthesized in Reference Example 21

(a) in dichloromethane (40 ml), 4.83 g of Dess-Martin

periodinane was added at room temperature with stirring

221102_G2572WO English Translation (Final) clean copy

under a stream of argon, and the mixture was stirred at

room temperature for 10 minutes.

After the completion of reaction, a saturated

aqueous solution of sodium bicarbonate supplemented with

sodium thiosulfate was added to the reaction solution,

and the mixed solution was subjected to extraction with

methylene chloride. The organic layer was washed with

saturated saline, dried over anhydrous magnesium sulfate,

filtered, and concentrated under reduced pressure. The

obtained residue was purified by medium-pressure

preparative chromatography (silica gel, eluting solvent:

hexane:ethyl acetate) to obtain 1.66 g of the title

compound as a colorless oil.

Mass spectrum (EI, m/z): 266 [M]+.

[0271] Reference Example 15-(b), etc.:

Corresponding starting compounds were treated in the

same manner as in Reference Example 21-(b) to obtain

compounds described in the following Table 9.

[0272]

Table 9 Reference Example Structural formula Mass spectrum 0

Reference Example (Cl, m/z): 227 [M+H]+ 15-(b) I C1 CF3 F

0 Reference Example 30-(b) F F F 0 0 F

221102_G2572WO English Translation (Final) clean copy

[0273] Reference Example 24-(a)

Production of 3-(difluoromethoxy)-5

(trifluoromethyl)benzaldehyde

0

F -O CF3

[0274] To a suspension of 4.36 g of potassium carbonate

in N,N-dimethylformamide (16 ml), a solution of 6.42 g of

sodium chlorodifluoroacetate and 4.00 g of 3-hydroxy-5

(trifluoromethyl)benzaldehyde in N,N-dimethylformamide

(20 ml) was added dropwise at 95°C under a stream of

argon, and the mixture was stirred at 95°C for 30

minutes.

After the completion of reaction, water was added to

the reaction mixture, and the mixed solution was

subjected to extraction with tert-butyl methyl ether.

The organic layer was washed with saturated saline, dried

over anhydrous magnesium sulfate, filtered, and

concentrated under reduced pressure. The obtained

residue was purified by medium-pressure preparative

chromatography (silica gel, eluting solvent: hexane:ethyl

acetate) to obtain 1.48 g of the title compound as a

colorless oil.

Mass spectrum (EI, m/z): 240 [M]+.

[0275] Reference Example 25-(a), etc.:

221102_G2572WO English Translation (Final) clean copy

Corresponding starting compounds were treated in the

same manner as in Reference Example 24-(a) to obtain

compounds described in the following Table 10.

[027 6]

Table 10 Reference Example Structural formula Mass spectrum

0 Reference Example (El, m/z): 206 [M]+ 25-(a) F (lmz:0[] Cl 0) F O Reference Example (El, m/z): 250, 252 [M]+ 26-(a) ~' F (lmz:5,5[ Br 0 F

Reference Example O F (El, m/z): 190 [M]+ 27-(a)0 F

F

O Reference Example F (El, m/z): 190 [M]+ 28-(a) F F (lmz:9[] F 0

[0277] Reference Example 1-(f)

Production of 2-fluoromalonamide

O 0

H2N NH2

[0278]

To a solution of 25.0 g of diethyl 2-fluoromalonate

in methanol (100 ml), 80 ml of a 7 N solution of ammonia

in methanol was added at room temperature under a stream

221102_G2572WO English Translation (Final) clean copy

of argon, and the mixture was stirred at room temperature

for 4 hours.

After the completion of reaction, a solid was

collected by filtration, washed with methanol, and then

dried under reduced pressure at 500C to obtain 15.91 g of

the title compound as a white solid.

'H-NMR spectrum (400MHz, DMSO-d 6 ) 6: 7.78 - 7.48 (m,

4H), 5.16 (d, J = 48.9 Hz, 1H).

[0279] Reference Example 1-(g)

Production of 2-fluoropropane-1,3-diamine hydrochloride

HCI

H 2N NH 2 F

[0280] To 400 ml of a 0.9 M solution of a borane

tetrahydrofuran complex in tetrahydrofuran, 7.20 g of 2

fluoromalonamide synthesized in Reference Example 1-(f)

was added in divided portions at room temperature under a

stream of argon, and the mixture was stirred at room

temperature for 20 hours.

After the completion of reaction, the reaction

mixture was cooled to 0°C, and 73 ml of methanol was

added dropwise thereto at 20°C or lower. The mixture was

stirred at room temperature for 1 hour and concentrated

under reduced pressure. 40 ml of ethanol was added to

the concentration residue, then 60 ml of a 2 M solution

of hydrogen chloride in ethanol was added thereto at 0°C,

and the mixture was stirred at room temperature for 3

221102_G2572WO English Translation (Final) clean copy

hours. A deposited solid was collected by filtration,

and the solid was dissolved in methanol and concentrated

under reduced pressure. To the obtained solution of 6.91

g of the solid in methanol (200 ml), 70 g of Amberlite

(IRA478RF CL) sequentially washed with 200 ml of water

and 200 ml of methanol was added at room temperature, and

the mixture was stirred at room temperature for 30

minutes. The reaction mixture was filtered, and the

filtrate was concentrated under reduced pressure to

obtain 4.55 g of the title compound as a white solid.

'H-NMR spectrum (400MHz, DMSO-d 6 +D 20) 6: 4.77 - 4.53

(m, 1H), 3.01 - 2.79 (m, 4H) .

[0281] Reference Example 48-(a)

Production of methyl 4-bromo-3-fluoro-1-(tetrahydropyran

2-yl)-1H-indazole-6-carboxylate

0

N-N

0

[0282] To a suspension of 200 mg of methyl 4-bromo-1H

indazole-6-carboxylate in acetonitrile (8 ml), 333 mg of

1-chloromethyl-4-fluoro-1,4-diazoniabicyclo[2.2.2]octane

bis(tetrafluoroborate) was added at room temperature

under a stream of argon, and the mixture was stirred at

1000C for 4 hours.

After the completion of reaction, water was added to

the reaction mixture, and the mixed solution was

221102_G2572WO English Translation (Final) clean copy

subjected to extraction with ethyl acetate. The organic

layer was washed with saturated saline, dried over

anhydrous sodium sulfate, filtered, and concentrated

under reduced pressure.

To a suspension of the obtained concentration

residue in dichloromethane (8 ml), 143 pl of 3,4-dihydro

2H-pyran and 15 mg of p-toluenesulfonic acid monohydrate

were added at room temperature under a stream of argon,

and the mixture was stirred at room temperature for 4

hours.

After the completion of reaction, a saturated

aqueous solution of sodium bicarbonate was added to the

reaction mixture, and the mixed solution was subjected to

extraction with dichloromethane. The organic layer was

washed with water, dried over anhydrous magnesium

sulfate, filtered, and concentrated under reduced

pressure. The obtained residue was subjected to medium

pressure preparative chromatography (silica gel, eluting

solvent: hexane:ethyl acetate), and a fraction containing

the compound of interest was concentrated under reduced

pressure.

The obtained residue was purified by gel permeation

chromatography (column: YMC-GPC T30000, YMC-GPC T4000,

and YMC-GPC T2000, eluting solvent: ethyl acetate) to

obtain 32 mg of the title compound as a white solid.

Mass spectrum (ESI, m/z): 357, 359 [M+H]+.

[0283] Reference Example 49-(a)

221102_G2572WO English Translation (Final) clean copy

Production of methyl 3-chloro-4-nitro-1H-indazole-6

carboxylate

0 2N

ClO N-NHi

[0284] To a suspension of 300 mg of methyl 4-nitro-1H

indazole-6-carboxylate in acetonitrile (8 ml), 217 mg of

N-chlorosuccinimide was added at room temperature under a

stream of argon, and the mixture was stirred at 800C for

2 hours. Next, 145 mg of N-chlorosuccinimide was further

added thereto at 80°C, and the mixture was stirred at

°C for 2 hours.

After the completion of reaction, the reaction

mixture was poured to a saturated aqueous solution of

sodium bicarbonate, and the mixed solution was subjected

to extraction with ethyl acetate. The organic layer was

washed with saturated saline, dried over anhydrous

magnesium sulfate, filtered, and concentrated under

reduced pressure to obtain 347 mg of the title compound

as a pale yellow solid.

Mass spectrum (ESI, m/z): 254 [M-H]-.

[0285] Reference Example 1-(h)

Production of methyl 4-bromo-l-(tetrahydropyran-2-yl)-1H

indazole-6-carboxylate

221102_G2572WO English Translation (Final) clean copy

0

[0286] To a suspension of 1.00 g of methyl 4-bromo-1H

indazole-6-carboxylate in dichloromethane (10 ml), 717 pl

of 3,4-dihydro-2H-pyran and 82 mg of p-toluenesulfonic

acid monohydrate were added at room temperature under a

stream of argon, and the mixture was stirred at room

temperature for 1 hour.

After the completion of reaction, a saturated

aqueous solution of sodium bicarbonate was added to the

reaction mixture, and the mixed solution was subjected to

extraction with dichloromethane. The organic layer was

washed with water, dried over anhydrous magnesium

sulfate, filtered, and concentrated under reduced

pressure. The obtained residue was purified by medium

pressure preparative chromatography (silica gel, eluting

solvent: hexane:ethyl acetate) to obtain 1.13 g of the

title compound as a pale yellow solid.

Mass spectrum (ESI, m/z): 339, 341 [M+H]+.

[0287] Reference Example 49-(b):

A corresponding starting compound was treated in the

same manner as in Reference Example 1-(h) to obtain a

compound described in the following Table 11.

221102_G2572WO English Translation (Final) clean copy

[ 02 8 8]

Table 11 Reference Example Structural formula Mass spectrum 0

Reernc Eamle 02 N Reference4Example c -1-0 (ESI, m/z): 340 [M+H]+ N-N

[0289] Reference Example 1-(i)

Production of methyl 4-((diphenylmethylene)amino)-1

(tetrahydropyran-2-yl)-1H-indazole-6-carboxylate

N-N 0

[0290] To a solution of 1.13 g of methyl 4-bromo-l

(tetrahydropyran-2-yl)-1H-indazole-6-carboxylate

synthesized in Reference Example 1-(h) in xylene (20 ml),

1.11 ml of benzophenone imine, 305 mg of

tris(dibenzylideneacetone)dipalladium(0), 771 mg of 4,5

bis(diphenylphosphino)-9,9-dimethylxanthene, and 3.26 g

of cesium carbonate were added at room temperature under

a stream of argon. After purging with an argon

atmosphere, the mixture was stirred at 150°C for 6 hours

under a stream of argon.

After the completion of reaction, a saturated

aqueous solution of ammonium chloride was added to the

reaction mixture, and the mixed solution was subjected to

221102_G2572WO English Translation (Final) clean copy

extraction with toluene. The organic layer was washed

with saturated saline, dried over anhydrous sodium

sulfate, filtered, and concentrated under reduced

pressure. The obtained residue was subjected to medium

pressure preparative chromatography (silica gel, eluting

solvent: hexane:ethyl acetate), and a fraction containing

the compound of interest was concentrated under reduced

pressure. 20 mL of tert-butyl methyl ether was added to

the obtained residue at room temperature, and the mixture

was stirred at room temperature for 1 hour. A solid was

collected by filtration to obtain 1.09 g of the title

compound as a yellow solid.

'H-NMR spectrum (400MHz, DMSO-d6 ) 6: 8.09 (d, J = 0.8

Hz, 1H), 7.90 - 7.87 (m, 1H), 7.78 - 7.70 (m, 2H), 7.62

7.46 (m, 3H), 7.28 - 7.17 (m, 5H), 6.91 (d, J = 1.1 Hz,

1H), 5.91 (dd, J = 2.3, 9.5 Hz, 1H), 3.89 - 3.72 (m, 5H),

2.40 - 2.29 (m, 1H), 2.04 - 1.92 (m, 2H), 1.80 - 1.68 (m,

1H), 1.61 - 1.49 (m, 2H).

[0291] Reference Example 48-(b):

A corresponding starting compound was treated in the

same manner as in Reference Example 1-(i) to obtain a

compound described in the following Table 12.

221102_G2572WO English Translation (Final) clean copy

[0292]

Table 12 Reference Example Structural formula Mass spectrum Ph Ph

Reference Example F (ESI, m/z): 458 [M+H]+ 48-(b) F v(SXlz:5[+] N-N

[0293] Reference Example 1-(j)

Production of methyl 4-amino-i-(tetrahydropyran-2-yl)-lH

indazole-6-carboxylate

0 H2N

I-N

[0294] To a solution of 890 mg of methyl 4

((diphenylmethylene)amino)-1-(tetrahydropyran-2-yl)-1H

indazole-6-carboxylate synthesized in Reference Example

1-(i) in tetrahydrofuran (30 ml), 970 mg of 5% palladium

carbon (containing 50.57% water, AER-type manufactured by

N.E. Chemcat Corp.) was added at room temperature under a

stream of argon. After purging with a hydrogen

atmosphere, the mixture was stirred at room temperature

for 1.5 hours.

After the completion of reaction, the reaction

mixture was filtered through celite and washed with ethyl

acetate, and the filtrate was concentrated under reduced

pressure. The obtained residue was purified by medium

221102_G2572WO English Translation (Final) clean copy

pressure preparative chromatography (silica gel, eluting

solvent: hexane:ethyl acetate) to obtain 523 mg of the

title compound as a white solid.

Mass spectrum (ESI, m/z): 276 [M+H]+.

[0295] Reference Example 48-(c)

Production of methyl 4-amino-3-fluoro-1-(tetrahydropyran

2-yl)-1H-indazole-6-carboxylate

H2N

F N-N

0

[0296] To a solution of 100 mg of methyl 4

((diphenylmethylene)amino)-3-fluoro-1-(tetrahydropyran-2

yl)-1H-indazole-6-carboxylate synthesized in Reference

Example 48-(b) in tetrahydrofuran (0.4 ml), 0.8 ml of a

% aqueous citric acid solution was added at room

temperature under a stream of argon, and the mixture was

stirred at 700C for 18 hours.

After the completion of reaction, a saturated

aqueous solution of sodium bicarbonate was added to the

reaction mixture, and the mixed solution was subjected to

extraction with ethyl acetate. The organic layer was

washed with saturated saline, dried over anhydrous sodium

sulfate, filtered, and concentrated under reduced

pressure. The obtained residue was purified by medium

pressure preparative chromatography (silica gel, eluting

221102_G2572WO English Translation (Final) clean copy

solvent: hexane:ethyl acetate) to obtain 53 mg of the

title compound as a yellow solid.

Mass spectrum (ESI, m/z): 294 [M+H]+.

[0297] Reference Example 49-(c)

Production of methyl 4-amino-3-chloro-1-(tetrahydropyran

2-yl)-1H-indazole-6-carboxylate

0

N-N 0

[0298] To a suspension of 304 mg of methyl 3-chloro-4

nitro-1-(tetrahydropyran-2-yl)-1H-indazole-6-carboxylate

synthesized in Reference Example 49-(b) in ethanol (3 ml)

and water (1.5 ml), 779 mg of sodium dithionite was added

at room temperature under a stream of argon, and the

mixture was stirred at 900C for 1 hour.

After the completion of reaction, the reaction

mixture was poured to water, and the mixed solution was

subjected to extraction with ethyl acetate. The organic

layer was washed with a saturated aqueous solution of

sodium bicarbonate, dried over anhydrous magnesium

sulfate, filtered, and concentrated under reduced

pressure. The obtained residue was purified by medium

pressure preparative chromatography (silica gel, eluting

solvent: hexane:ethyl acetate) to obtain 131 mg of the

title compound as a pale yellow solid.

Mass spectrum (ESI, m/z): 310 [M+H]+.

221102_G2572WO English Translation (Final) clean copy

[0299] Reference Example 1-(k)

Production of methyl 4-(3-methylthioureido)-l

(tetrahydropyran-2-yl)-1H-indazole-6-carboxylate

P0 H

[0300] To a solution of 200 mg of methyl 4-amino-1

(tetrahydropyran-2-yl)-1H-indazole-6-carboxylate

synthesized in the same manner as in Reference Example 1

(j) in N-methylpyrrolidone (2 ml), 133 mg of methyl

isothiocyanate and 200 ptl of acetic acid were added at

room temperature under a stream of argon, and the mixture

was stirred at 1000C for 9 hours.

After the completion of reaction, water was added to

the reaction mixture, and the mixed solution was

subjected to extraction with ethyl acetate. The organic

layer was washed with saturated saline, dried over

anhydrous magnesium sulfate, filtered, and concentrated

under reduced pressure. The obtained residue was

purified by medium-pressure preparative chromatography

(silica gel, eluting solvent: hexane:ethyl acetate) to

obtain 184 mg of the title compound as a white solid.

Mass spectrum (ESI, m/z): 349 [M+H]+.

[0301] Reference Example 48-(d), etc.:

221102_G2572WO English Translation (Final) clean copy

Corresponding starting compounds were treated in the

same manner as in Reference Example 1-(k) to obtain

compounds described in the following Table 13.

[0302]

Table 13 Reference Example Structural formula Mass spectrum

HN S

Reference Example HN (ESI, m/z): 367 [M+H]+ 48-(d) F(EIm )36[+] N-N

HN S

Reference Example cH o (ESI, m/z): 383

[M+H]+ 49-(d) ci(EIm )38[+] N-N

0

[0303] Reference Example 52-(a)

Production of methyl 6-(3-methylthioureido)-lH-indazole

4-carboxylate

H- H C C YN

[0304] To a solution of 500 mg of methyl 6-amino-lH

indazole-4-carboxylate in N-methylpyrrolidone (2.5 ml),

233 mg of methyl isothiocyanate was added at room

temperature under a stream of argon, and the mixture was

stirred at room temperature for 2 hours, left standing at

room temperature for 84 hours, and stirred at 70°C for 7

hours.

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After the completion of reaction, water was added to

the reaction mixture, and the mixture was stirred at room

temperature for 15 minutes. A deposited solid was

collected by filtration, washed with water, and then

dried under reduced pressure at 600C to obtain 408 mg of

the title compound as a pale yellow solid.

Mass spectrum (ESI, m/z): 265 [M+H]+.

[0305] Reference Example 1-(l)

Production of 4-(3-methylthioureido)-1H-indazole-6

carboxylic acid

Y OH S W N-NH

[0306] To a suspension of 4.81 g of methyl 4-(3

methylthioureido)-1-(tetrahydropyran-2-yl)-1H-indazole-6

carboxylate synthesized in the same manner as in

Reference Example 1-(k) in methanol (69.2 ml), 17.3 ml of

a 4 M solution of hydrogen chloride in 1,4-dioxane was

added at room temperature under a stream of argon, and

the mixture was stirred at room temperature for 6 hours.

After the completion of reaction, the reaction

mixture was concentrated under reduced pressure,

subjected to azeotropy with 30 ml of tert-butyl methyl

ether, and dried under reduced pressure at 50°C.

To a suspension of the obtained residue in methanol

(41.4 ml), 41.4 ml of a 1 M aqueous sodium hydroxide

solution was added at room temperature under a stream of

221102_G2572WO English Translation (Final) clean copy

argon, and the mixture was stirred at room temperature

for 3 hours.

After the completion of reaction, the reaction

mixture was adjusted to pH 4.0 by the addition of 2 M

hydrochloric acid, and the mixture was stirred at room

temperature for 1 hour. A deposited solid was collected

by filtration, washed with water, and then dried under

reduced pressure at 60°C to obtain 2.80 g of the title

compound as a pale yellow solid.

Mass spectrum (ESI, m/z): 251 [M+H]+.

[0307] Reference Example 49-(e)

Production of methyl 3-chloro-4-(3-methylthioureido)-1H

indazole-6-carboxylate

HN S

C1 N-NH

[0308] To a suspension of 840 mg of methyl 3-chloro-4-(3

methylthioureido)-1-(tetrahydropyran-2-yl)-1H-indazole-6

carboxylate synthesized in the same manner as in

Reference Example 49-(d) in dichloromethane (5 ml), 2.52

ml of trifluoroacetic acid was added dropwise at room

temperature under a stream of argon, and the mixture was

stirred at room temperature for 10 hours.

After the completion of reaction, the reaction

mixture was concentrated under reduced pressure. The

obtained residue was purified by medium-pressure

221102_G2572WO English Translation (Final) clean copy

preparative chromatography (silica gel, eluting solvent:

hexane:ethyl acetate) to obtain 375 mg of the title

compound as a pale yellow solid.

Mass spectrum (ESI, m/z): 299 [M+H]+.

[0309] Reference Example 48-(e)

Production of 3-fluoro-4-(3-methylthioureido)-1

(tetrahydropyran-2-yl)-1H-indazole-6-carboxylic acid

kN5

HNH F N-N

[0310] To a suspension of 245 mg of methyl 3-fluoro-4-(3

methylthioureido)-1-(tetrahydropyran-2-yl)-1H-indazole-6

carboxylate synthesized in the same manner as in

Reference Example 48-(d) in methanol (2 ml), 2 ml of a 1

M aqueous sodium hydroxide solution and 3 ml of

tetrahydrofuran were added at room temperature under a

stream of argon, and the mixture was stirred at room

temperature for 2 hours.

After the completion of reaction, the reaction

mixture was adjusted to pH 4.0 by the addition of 1 M

hydrochloric acid, and the mixture was stirred at room

temperature for 1 hour. The reaction mixture was

concentrated under reduced pressure, and tetrahydrofuran

was distilled off under reduced pressure. The residue

was stirred at room temperature for 15 hours. A

deposited solid was collected by filtration, washed with

221102_G2572WO English Translation (Final) clean copy

water, and then dried under reduced pressure at 600C to

obtain 202 mg of the title compound as a white solid.

Mass spectrum (ESI, m/z): 353 [M+H]+.

[0311] Reference Example 49-(f)

Production of 3-chloro-4-(3-methylthioureido)-1H

indazole-6-carboxylic acid

I HN S

HN ~OH CI N-NH

[0312] To a suspension of 337 mg of methyl 3-chloro-4-(3

methylthioureido)-1H-indazole-6-carboxylate synthesized

in Reference Example 49-(e) in methanol (4.2 ml), 1.69 ml

of a 2 M aqueous sodium hydroxide solution was added

dropwise at room temperature, and the mixture was stirred

at room temperature for 5 hours.

After the completion of reaction, the reaction

mixture was adjusted to pH 4 by the addition of 2 M

hydrochloric acid, and the mixture was stirred at room

temperature for 0.5 hours. A deposited solid was

collected by filtration and dried under reduced pressure

to obtain 110 mg of the title compound as a pale yellow

solid.

Mass spectrum (ESI, m/z): 285 [M+H]+.

[0313] Reference Example 52-(b):

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A corresponding starting compound was treated in the

same manner as in Reference Example 49-(f) to obtain a

compound described in the following Table 14.

[0314]

Table 14 Reference Example Structural formula Mass spectrum

H H O Reference Example -N N OH (ESI, m/z): 251 [M+H]+ 52-(b) S HN-N

[0315] Reference Example 1-(m)

Production of 4-((5-fluoro-1,4,5,6-tetrahydropyrimidin-2

yl)amino)-1H-indazole-6-carboxylic acid

HH

[0316] To a solution of 10.00 g of 4-(3

methylthioureido)-1H-indazole-6-carboxylic acid

synthesized in the same manner as in Reference Example 1

(1) in N-methylpyrrolidone (100 ml), 3.00 ml of

iodomethane was added at room temperature under a stream

of argon, and the mixture was stirred at room temperature

for 16 hours. The pressure of the reaction mixture was

reduced, and excess iodomethane was removed. 10.27 g of

2-fluoropropane-1,3-diamine hydrochloride synthesized in

the same manner as in Reference Example 1-(g) and 17 ml

of water were added to the obtained solution at room

temperature, and the mixture was stirred at 1100C for 8

221102_G2572WO English Translation (Final) clean copy

hours, stirred at room temperature for 13 hours, stirred

at 110°C for 11 hours, stirred at room temperature for 13

hours, and stirred at 110°C for 9 hours.

After the completion of reaction, 283 ml of water

was added to the reaction mixture, and the mixture was

stirred at room temperature for 15 hours. A deposited

solid was collected by filtration, washed with water, and

then dried under reduced pressure at 600C to obtain 7.40

g of the title compound as a white solid.

Mass spectrum (ESI, m/z): 278 [M+H]+.

[0317] Reference Example 48-(f), etc.:

Corresponding starting compounds were treated in the

same manner as in Reference Example 1-(m) to obtain

compounds described in the following Table 15.

[0318]

Table 15 Reference Example Structural formula Mass spectrum F

HN N O Reference Example HN OH (ESI, m/z): 380 [M+H]+ 48-(f)N N-N

F

Reference Example HN N O (ESI, m/z): 312 [M+H]+ 49-(g) HN OH CI N-NH

H H O Reference Example N N OH (ESI, m/z): 278 [M+H]+ 52-(c) F N

HN-N

221102_G2572WO English Translation (Final) clean copy

[0319] Reference Example 50-(a)

Production of 4-((5-hydroxy-1,4,5,6-tetrahydropyrimidin

2-yl)amino)-1H-indazole-6-carboxylic acid

H H H N N, OH NNH

[0320] To a solution of 1.00 g of 4-(3-methylthioureido)

1H-indazole-6-carboxylic acid synthesized in the same

manner as in Reference Example 1-(l) in N

methylpyrrolidone (10 ml), 0.30 ml of iodomethane was

added at room temperature under a stream of argon, and

the mixture was stirred at room temperature for 2 hours.

The pressure of the reaction mixture was reduced, and

excess iodomethane was removed. 1.08 g of 1,3

diaminopropan-2-ol was added to the obtained solution at

room temperature, and the mixture was stirred at 110°C

for 6 hours.

After the completion of reaction, the reaction

mixture was cooled to room temperature and stirred at

room temperature for 17 hours. 10 ml of water was added

thereto, and the mixture was stirred at room temperature

for 4 hours. A deposited solid was collected by

filtration, washed with water, and then dried under

reduced pressure to obtain 915 mg of the title compound

as a white solid.

Mass spectrum (ESI, m/z): 276 [M+H]+.

221102_G2572WO English Translation (Final) clean copy

[0321] Reference Example 51-(a):

A corresponding starting compound was treated in the

same manner as in Reference Example 50-(a) to obtain a

compound described in the following Table 16.

[0322]

Table 16 Reference Example Structural formula Mass spectrum

H H Reference Example N NOH (ESI,m/z):260[M+H]+ 51 -(a) NH (Smz:20[+l

N-NH

[0323] Reference Example 48-(g)

Production of 3-fluoro-4-((5-fluoro-1,4,5,6

tetrahydropyrimidin-2-yl)amino)-lH-indazole-6-carboxylic

acid F

HcI

F H F N-NH

[0324] To 110 mg of 3-fluoro-4-((5-fluoro-1,4,5,6

tetrahydropyrimidin-2-yl)amino)-1-(tetrahydropyran-2-yl)

1H-indazole-6-carboxylic acid synthesized in the same

manner as in Reference Example 48-(f), 2.9 ml of 1 M

hydrochloric acid was added at room temperature under a

stream of argon, and the mixture was stirred at 60°C for

11 hours and stirred at room temperature for 13 hours.

Subsequently, 1.45 ml of 1 M hydrochloric acid was added

221102_G2572WO English Translation (Final) clean copy

thereto at room temperature, and the mixture was stirred

at 700C for 9 hours and stirred at room temperature for

18 hours.

After the completion of reaction, a solid was

collected by filtration, washed with water, and then

dried under reduced pressure at 600C to obtain 74 mg of

the title compound as a white solid.

Mass spectrum (ESI, m/z): 296 [M+H]+.

[0325] Example 1-(a)

Production of methyl (3S)-3-(3-chloro-5

(trifluoromethyl)phenyl)-3-(2-(4-((5-fluoro-1,4,5,6

tetrahydropyrimidin-2-yl)amino)-1H-indazole-6

carboxamido)acetamido)propanoate trifluoroacetate

0 H H 0 H N N N O0 F3C'OH F O N-NH CF 3

[0326] To a suspension of 80 mg of methyl (S)-3-(2

aminoacetamido)-3-(3-chloro-5

(trifluoromethyl)phenyl)propanoate hydrochloride

synthesized in the same manner as in Reference Example 1

(e) and 65 mg of 4-((5-fluoro-1,4,5,6

tetrahydropyrimidin-2-yl)amino)-1H-indazole-6-carboxylic

acid synthesized in the same manner as in Reference

Example 1-(m) in N,N-dimethylformamide (1 ml), 38 mg of

1-hydroxybenzotriazole was added at room temperature

under a stream of argon, and the mixture was stirred at

221102_G2572WO English Translation (Final) clean copy

room temperature for 10 minutes. Subsequently, 0.043 ml

of N,N'-diisopropylcarbodiimide was added thereto at room

temperature, and the mixture was stirred at room

temperature for 5 hours.

After the completion of reaction, the reaction

mixture was purified by medium-pressure preparative

chromatography (ODS, eluting solvent: 0.1% aqueous

trifluoroacetic acid solution:0.1% solution of

trifluoroacetic acid in acetonitrile) to obtain 132 mg of

the title compound as a pale yellow solid.

Mass spectrum (ESI, m/z): 598 [M+H]+.

[0327] Example 2-(a), etc.:

Corresponding starting compounds were treated in the

same manner as in Example 1-(a) to obtain compounds

described in the following Tables 17-1 to 17-7.

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[ 0 32 8]

Table 17-1

Example Structural formula Mass spectrum

H H B C Example F 3C OH NN O

N-Br CF 3 0 H H 0 H N-NHCF Example Example F3C OH F30HF NO NN (ESI, m/z): 5786 [M+H]+ OmN

3E(amp) F N O (ESI, m/z): 690 [M+H]+ H I CF 3

0 H H 0 H Example F 3C OH N N (S m/z) 62 [ Xap F N O (ESI, m/z): 578 [M+H]+ N-NH CF 3

0 H H 0 H Example F3C) OH N N N ' N 01 -(a) FU NF O F (ESI, m/z): 594 [M+H]+ N-NH 0 CF 3

H H192 Exml FkO N- N 0 FCC Fxml N H 0 (ESI, mlz): 582 [M+H]+ 6-(a) FC NH F CF 3

O H H 0 H Example F3 C" OH NN ANIY 7-() N0 0 (ESI, mlz): 632 [M+H]+ NH F3C CF 3 oH HwH

Example 3 ~H y H N 0 .- (ESI, mlz): 630 [M+H]+ 8-(a) F N-NH IC2 0N

O H H 0 H NIN N Example F3C OH Ij- H CO2 ESmz:52[H] 9-(a) F N0 F

NH CF 3

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[ 0 32 9 ]

Table 17-2

Example Structural formula Mass spectrum

0 H H N 0~ Example F3C OH F jN-' NH C0 2Me

+ Exame C F N (ESI, m/z): 598 [M+H]+ N-NH CF 3

0 H H O Example F3 C) O N NYN O2 M Examl F F N 0 FO (ESI, m/z): 582 [M+H]+ F3C

0 H H O Example 3F C OH f N N o ES FaC OF N N (ESI, m/z): 598 [M+H]+ N--NH CF3 PNH )'F3C

0 C H HN 0y ON

Example 3N OH I H p3(a) e F3C OH F O (ESI, m/z): 582 [M+H]+ CF 3

0 H H 0 H

F3C'OH N N N N 0 Example 14()FU N-N 0 0 (ESI, mlz): 578 [M+H]+ CF 3

Example IN OH HH0N

15-(a) F3CO N Io" (ESI, mlz): 616 [M+H]+ CI CF 3 F

0 H H 0 H

Example F3 C OH N' NN N 16()FU PH 0 1. 0 (ESI, mlz): 604,606 [M+H]+ 16-() N-H NBr

0 H H 0 H Exmpe 3 CkO ExmleFC NN N ~ O HC (ESI, mlz): 564 [M+H]+ N7-NH N 0 0

221102_G2572W0 English Translation (Final) clean copy

[ 033 0]

Table 17-3 Example Structural formula Mass spectrum

0 H H 0 H ExamplNF 3 CyO Ny0, 18-(a) F Nxml F3 O 0 0 (ESI, mlz): 608, 610 [M+H]+ N-HBr cI

0 H H 0 H Example F3C OH HEImz: 5N[+] 19-(a) F N 0 (E0mz:5[+] N-NH -!

NH Br Br

0 H H 0 H Example F3C OH H EI mz:70,0 [f] 20-(a) F N 0 0EImz:0,0[+] N-NH: NHBr I

0 H H 0 H Exaple F3 COH H (ESI, mlz): 656 [M+H]+ 21 -(a) F NNH ci I

O H H 0 H

NNH

0 H H 0 H Example F3C k OH NyNp N"'SN CO 2Me 23-(a F N 0 (ESI, mlz): 592, 594 [M+H]+ NNH Br

0 H H 0 H Example F3 c lOH N AN NI- N4(a F N 0 (ESI, mlz): 630 [M+H]+ NNH FO " CF 3

0 H H 0 H Example F3 C~ NHN (EI /) 56[+ 25-(a) F N 0 0. F (S~lz:9[+]

221102_G2572WO English Translation (Final) clean copy

[ 0 3 31]

Table 17-4

Example Structural formula Mass spectrum

0 H H 0 H Example F3CAOH N:N604[+ Ex-a)l FCO F O (ESI, m/z): 640,642[M+H] N-NH O F Br 0 F

Example F3C OH F (ES 6 Exam F N O (ESI, m/z): 614 [M+H]+ N-NH C OAF F

0 H H 0 H Example F3 H (E0 m/)H28[+] Example F3C OH N N (ESI,m/z):580[M+H]+ F H --- N N H F N N

28-(a) NH HF N-NH 0 F

0 H H 0 H Example F3C'kOH NyN - N 0 29-(a) F N\ 0 F (ESI, mlz): 628 [M+H]+ NH 0-- F ,

0 H H 0 H

30-(a) N N NNH N- )

Example F 3C OH FHN (ESI, m/z): 618 [M+H]+

Example F 3C OH NN N N? 0 (ESI, mlz):658,66[M+H] N 0- N2(a H H H195 BHrc OCF 3

0 H H 0 H F~&O N N N CO, Example F3 CH FCO CF +P

32-(a) 0 (ESI, mlz):58,0[M+H] FIU

NNH H

N-H F 3CO

221102_G2572WO English Translation (Final) clean copy

[0332]

Table 17-5

Example Structural formula Mass spectrum

H H N H

Example F3C OH F N N (ESI, m/z): 598 [M+H]+ N-NH N OCF 3 F

0 H H

Example F3C OH N N ?[N 35-(a) FIN H~ 0 0 (ESI, mlz): 564 [M+H]+ N-NH CF 3

0 H H Example F3C~ NP N-N rO E eO N N O (ESI, m/z): 580 [M+H]+ N-NH OCF 3

Example F3C 'OH F (EN m /zOM Ex-aml FCO F N (ESI, m/z): 562 [M+H]+ -NH C OH

0 H H 0 H

Example F3C OHF N (ESI,m/z):546[M+H]+

N-NH F. Example F3C OH F N IN ON (ESI, m/z): 536 [M+H]+ 3--(a) 16 0 H H 1 1 Example F 3 C OH NNP N N

39(a Z N(a Ff .- (ESI, mlz): 552[M+H]+

0 H H 0 H Example F 3C OH Ny N N~N 1 41(a F NH (ESI, mlz): 530[M+H]+ NNH N. "L

0~ 19 H -

221102_G2572WO English Translation (Final) clean copy

[ 0 3 3 3]

Table 17-6

Example Structural formula Mass spectrum

0 H H 0 H Example F3C OH F N N (ESI, m/z): 574,576 [M+H]+

N-NH Br

O H H

Example F3 C OH NyN OrN (5 FN 0 (ESI, m/z): 562 [M+H]+ 43-(a) F NH N

F3 C ) OH N0 Example F F N O (ESI,mz):590[M+H]+

O O

Example F3C OHF N O (ESI, m/z): 564 [M+H]+ N-NH N 0o 0 H

45-(a) \N-F NZi (ESI, mlz): 562[M+H]+ Example F3C OH H ON H- HI

N N N~y ON

Ex-a)pl F N0 0 0 (ESI, mlz): 564 [M+H]+ 46()N-NHN

Fr

Example F IH~y H 47-(a Ff i, W\0 1 0 (ESI, mlz):66[M+H]+ N-NH N CICF 3 H~j- 19 -~

F 9

221102_G2572WO English Translation (Final) clean copy

[0334]

Table 17-7

Example Structural formula Mass spectrum F

Examplo N, F3C)'OH H 0 H (ESI, m/z): 632 [M+H]+ N--)N 0 N-NH CI CF 3

O H H CF3 Example F3C OH HN OK (ESI, m/z): 596 [M+H]+ 50-(a) NO 0N

NH CF 3 O H H H Example F3C OH NN O ON (ESIm/z):58rM+H]+ HN- Cl CF3

N-N ci CF3

H H198 Example F3c OH NN ~ NH N-N g Br C c (ESI, mlz): 598 [M+H]+ 52-(a) F N/ HN-N 'N- CF

0 H H 0 H Example F 3C ) OH N N N N0, 'N

53-a) N -H (ESI, mlz): 642,644 [M+H]+ N-N C" HNN Br CF 3 Ex -a)pe FCO N N\ O0 (ESI, m/z): 564 [M+H]+ O H H 0 H Example 1 F3C ' "'OH N N N -N F NN4(a 0 (ESI, mlz): 690 [M+H]+ HNN I CF 3

O H H 0 H F~ N N N 0N Exmpe 3COH f j- H0 (EIm)58[+] Nxml N6Y 55-(a) F N 0 I E I /z:52[+ ] HN-N "NCF 3

0 H H 0 H Example F3C OH NN Ir F N6(a N0 (ESI, mlz): 564 [M+H]+ HN-N "NCF3

221102_G2572WO English Translation (Final) clean copy

[0335] Example 1-(b)

Production of (3S)-3-(3-chloro-5

(trifluoromethyl)phenyl)-3-(2-(4-((5-fluoro-1,4,5,6

tetrahydropyrimidin-2-yl)amino)-1H-indazole-6

carboxamido)acetamido)propanoic acid

H H O H N N N OH N N H o O F N-NH Cl C 3 I CF 3

[0336] To a suspension of 130 mg of methyl (3S)-3-(3

chloro-5-(trifluoromethyl)phenyl)-3-(2-(4-((5-fluoro

1,4,5,6-tetrahydropyrimidin-2-yl)amino)-1H-indazole-6

carboxamido)acetamido)propanoate trifluoroacetate

synthesized in Example 1-(a) in acetonitrile (1.5 ml) and

water (1.5 ml), 22 mg of lithium hydroxide was added at

room temperature under a stream of argon, and the mixture

was stirred at room temperature for 1 hour.

After the completion of reaction, the reaction

mixture was filtered. The filtrate was adjusted to pH

5.2 by the addition of 1 N hydrochloric acid, and the

mixture was stirred at room temperature for 2 hours. A

deposited solid was collected by filtration, washed with

water, and then dried under reduced pressure at 600C to

obtain 58 mg of the title compound as a white solid.

Mass spectrum (ESI, m/z): 584 [M+H]+.

221102_G2572WO English Translation (Final) clean copy

'H-NMR spectrum (400MHz, CD 30D) 6: 8.09 - 8.06 (m,

2H), 7.70 - 7.67 (m, 1H), 7.66 - 7.63 (m, 1H), 7.54

7.50 (m, 2H), 5.30 - 5.13 (m, 2H), 4.18 - 4.05 (m, 2H),

3.72 - 3.45 (m, 4H), 2.74 - 2.60 (m, 2H).

[0337] Example 2-(b)

Production of (3S)-3-(3-bromo-5-(trifluoromethyl)phenyl)

3-(2-(4-((5-fluoro-1,4,5,6-tetrahydropyrimidin-2

yl)amino)-1H-indazole-6-carboxamido)acetamido)propanoic

acid

H H H N N N INf CU 2 IF N-NH Br CF3

[0338] To a solution of 193 mg of methyl (3S)-3-(3-bromo

-(trifluoromethyl)phenyl)-3-(2-(4-((5-fluoro-1,4,5,6

tetrahydropyrimidin-2-yl)amino)-1H-indazole-6

carboxamido)acetamido)propanoate trifluoroacetate

synthesized in Example 2-(a) in acetonitrile (3 ml) and

water (3 ml), 31 mg of lithium hydroxide was added at

room temperature under a stream of argon, and the mixture

was stirred at room temperature for 3 hours.

Subsequently, 36 mg of lithium hydroxide was further

added thereto at room temperature, and the mixture was

stirred at room temperature for 1 hour.

After the completion of reaction, the reaction

mixture was adjusted to pH 5.8 by the addition of 1 N

hydrochloric acid, and the mixture was stirred at room

221102_G2572WO English Translation (Final) clean copy

temperature for 16 hours. A deposited solid was

collected by filtration, washed with water, and then

dried under reduced pressure at 60°C to obtain 107 mg of

the title compound as a white solid.

Mass spectrum (ESI, m/z): 628, 630 [M+H]+.

'H-NMR spectrum (400MHz, CD 30D) 6: 8.10 - 8.05 (m,

2H), 7.86 - 7.81 (m, 1H), 7.71 - 7.64 (m, 2H), 7.51 (d, J

= 1.1 Hz, 1H), 5.31 - 5.12 (m, 2H), 4.18 - 4.05 (m, 2H),

3.73 - 3.43 (m, 4H), 2.73 - 2.60 (m, 2H).

[0339] Example 3-(b)

Production of (3S)-3-(2-(4-((5-fluoro-1,4,5,6

tetrahydropyrimidin-2-yl)amino)-1H-indazole-6

carboxamido)acetamido)-3-(3-iodo-5

(trifluoromethyl)phenyl)propanoic acid

H H 0 H N N N N OH

F N 0O

N-NH CF3

[0340] To a solution of 79 mg of methyl (3S)-3-(2-(4-((5

fluoro-1,4,5,6-tetrahydropyrimidin-2-yl)amino)-1H

indazole-6-carboxamido)acetamido)-3-(3-iodo-5

(trifluoromethyl)phenyl)propanoate trifluoroacetate

synthesized in Example 3-(a) in acetonitrile (1.5 ml) and

water (1.5 ml), 12 mg of lithium hydroxide was added at

room temperature under a stream of argon, and the mixture

was stirred at room temperature for 1.5 hours.

221102_G2572WO English Translation (Final) clean copy

After the completion of reaction, the reaction

mixture was adjusted to pH 5.4 by the addition of 1 N

hydrochloric acid, and the mixture was stirred at room

temperature for 1 hour. A deposited solid was collected

by filtration, washed with water, and then dried under

reduced pressure at 600C to obtain 35 mg of the title

compound as a white solid.

Mass spectrum (ESI, m/z): 676 [M+H]+.

'H-NMR spectrum (400MHz, CD 30D) 6: 8.09 - 8.05 (m,

2H), 8.03 - 8.00 (m, 1H), 7.84 - 7.81 (m, 1H), 7.72

7.69 (m, 1H), 7.52 - 7.49 (m, 1H), 5.29 - 5.13 (m, 2H),

4.18 - 4.04 (m, 2H), 3.71 - 3.44 (m, 4H), 2.73 - 2.57 (m,

2H).

[0341] Example 4-(b)

Production of (3S)-3-(2-(4-((5-fluoro-1,4,5,6

tetrahydropyrimidin-2-yl)amino)-1H-indazole-6

carboxamido)acetamido)-3-(3-methyl-5

(trifluoromethyl)phenyl)propanoic acid

H H O H N N N N OH

F N 0 0

N-NH CF 3

[0342] To a solution of 97 mg of methyl (3S)-3-(2-(4-((5

fluoro-1,4,5,6-tetrahydropyrimidin-2-yl)amino)-1H

indazole-6-carboxamido)acetamido)-3-(3-methyl-5

(trifluoromethyl)phenyl)propanoate trifluoroacetate

synthesized in Example 4-(a) in acetonitrile (1 ml) and

221102_G2572WO English Translation (Final) clean copy

water (1 ml), 17 mg of lithium hydroxide was added at

room temperature under a stream of argon, and the mixture

was stirred at room temperature for 1.5 hours.

After the completion of reaction, the reaction

mixture was adjusted to pH 5.8 by the addition of 1 N

hydrochloric acid, and the mixture was filtered. The

filtrate was stirred at room temperature for 17 hours,

and a deposited solid was collected by filtration, washed

with water, and then dried under reduced pressure at 600C

to obtain 46 mg of the title compound as a white solid.

Mass spectrum (ESI, m/z): 564 [M+H]+.

'H-NMR spectrum (400MHz, CD 30D) 6: 8.09 (d, J = 0.9 Hz, 1H), 8.08 - 8.06 (m, 1H), 7.51 (d, J = 1.3 Hz, 1H),

7.49 - 7.45 (m, 2H), 7.33 - 7.30 (m, 1H), 5.30 - 5.14 (m,

2H), 4.19 - 4.04 (m, 2H), 3.73 - 3.45 (m, 4H), 2.75

2.63 (m, 2H), 2.39 (s, 3H).

[0343] Example 5-(b)

Production of (3S)-3-(2-(4-((5-fluoro-1,4,5,6

tetrahydropyrimidin-2-yl)amino)-lH-indazole-6

carboxamido)acetamido)-3-(3-methoxy-5

(trifluoromethyl)phenyl)propanoic acid

H H O H N N N CO 2H N H N-NH 1O CF3

[0344] To a solution of 183 mg of methyl (3S)-3-(2-(4

((5-fluoro-1,4,5,6-tetrahydropyrimidin-2-yl)amino)-1H

221102_G2572WO English Translation (Final) clean copy

indazole-6-carboxamido)acetamido)-3-(3-methoxy-5

(trifluoromethyl)phenyl)propanoate trifluoroacetate

synthesized in Example 5-(a) in acetonitrile (1 ml) and

water (1 ml), 24 mg of lithium hydroxide was added at

room temperature under a stream of argon, and the mixture

was stirred at room temperature for 2 hours.

After the completion of reaction, the reaction

mixture was filtered. The filtrate was adjusted to pH

5.5 by the addition of 1 N hydrochloric acid, and the

mixture was stirred at room temperature for 2 hours. A

deposited solid was collected by filtration, washed with

water, and then dried under reduced pressure at 600C to

obtain 44 mg of the title compound as a white solid.

Mass spectrum (ESI, m/z): 580 [M+H]+.

'H-NMR spectrum (400MHz, CD 3 0D) 6: 8.11 - 8.00 (m,

2H), 7.51 - 7.45 (m, 1H), 7.28 - 7.17 (m, 2H), 7.02

6.96 (m, 1H), 5.29 - 5.10 (m, 2H), 4.18 (d, J = 16.8 Hz,

1H), 4.05 (d, J = 16.8 Hz, 1H), 3.83 (s, 3H), 3.70 - 3.40

(m, 4H), 2.77 - 2.57 (m, 2H).

[0345]

Example 6-(b)

Production of (3S)-3-(2-(4-((5-fluoro-1,4,5,6

tetrahydropyrimidin-2-yl)amino)-1H-indazole-6

carboxamido)acetamido)-3-(3-fluoro-5

(trifluoromethyl)phenyl)propanoic acid

221102_G2572WO English Translation (Final) clean copy

H H H N N N OH

F N H F N-NH F CF 3

[0346] To a solution of 163 mg of methyl (3S)-3-(2-(4

((5-fluoro-1,4,5,6-tetrahydropyrimidin-2-yl)amino)-1H

indazole-6-carboxamido)acetamido)-3-(3-fluoro-5

(trifluoromethyl)phenyl)propanoate trifluoroacetate

synthesized in Example 6-(a) in acetonitrile (1 ml) and

water (1 ml), 28 mg of lithium hydroxide was added at

room temperature under a stream of argon, and the mixture

was stirred at room temperature for 3.5 hours.

After the completion of reaction, 1 ml of water was

added to the reaction mixture. The reaction mixture was

adjusted to pH 5.6 by the addition of 1 N hydrochloric

acid, and the mixture was stirred at room temperature for

hours. A deposited solid was collected by filtration,

washed with water, and then dried under reduced pressure

at 600C to obtain 66 mg of the title compound as a white

solid.

Mass spectrum (ESI, m/z): 568 [M+H]+.

'H-NMR spectrum (400MHz, CD 30D) 6: 8.09 - 8.05 (m,

2H), 7.56 - 7.53 (m, 1H), 7.50 (d, J = 1.1 Hz, 1H), 7.46

- 7.41 (m, 1H), 7.29 - 7.24 (m, 1H), 5.30 - 5.12 (m, 2H),

4.18 - 4.05 (m, 2H), 3.70 - 3.45 (m, 4H), 2.75 - 2.60 (m,

2H).

[0347] Example 7-(b)

221102_G2572WO English Translation (Final) clean copy

Production of (3S)-3-(3,5-bis(trifluoromethyl)phenyl)-3

(2-(4-((5-fluoro-1,4,5,6-tetrahydropyrimidin-2-yl)amino)

1H-indazole-6-carboxamido)acetamido)propanoic acid

H H H N N N OH ,UN F N-NH F3 C CF 3

[0348] To a solution of 130 mg of methyl (3S)-3-(3,5

bis(trifluoromethyl)phenyl)-3-(2-(4-((5-fluoro-1,4,5,6

tetrahydropyrimidin-2-yl)amino)-1H-indazole-6

carboxamido)acetamido)propanoate trifluoroacetate

synthesized in Example 7-(a) in acetonitrile (1 ml) and

water (1 ml), 21 mg of lithium hydroxide was added at

room temperature under a stream of argon, and the mixture

was stirred at room temperature for 2.5 hours.

After the completion of reaction, 1 ml of water was

added to the reaction mixture. The reaction mixture was

adjusted to pH 5.6 by the addition of 1 N hydrochloric

acid, and the mixture was stirred at room temperature for

hours. A deposited solid was collected by filtration,

washed with water, and then dried under reduced pressure

at 600C to obtain 87 mg of the title compound as a gray

solid.

Mass spectrum (ESI, m/z): 618 [M+H]+.

'H-NMR spectrum (400MHz, CD 30D) 6: 8.09 - 8.05 (m,

2H), 8.01 - 7.98 (m, 2H), 7.81 - 7.78 (m, 1H), 7.52

7.49 (m, 1H), 5.35 (t, J= 5.3 Hz, 1H), 5.30 - 5.12 (m,

221102_G2572WO English Translation (Final) clean copy

1H), 4.16 (d, J = 16.8 Hz, 1H), 4.07 (d, J = 16.8 Hz,

1H), 3.70 - 3.45 (m, 4H), 2.78 - 2.63 (m, 2H).

[0349] Example 8-(b)

Production of (3S)-3-(3-(1H-pyrazol-1-yl)-5

(trifluoromethyl)phenyl)-3-(2-(4-((5-fluoro-1,4,5,6

tetrahydropyrimidin-2-yl)amino)-lH-indazole-6

carboxamido)acetamido)propanoic acid

H H O H N N N CO 2H

F N 0 N-NH .. F3C N N

[0350] To a solution of 150 mg of methyl (3S)-3-(3-(1H

pyrazol-1-yl)-5-(trifluoromethyl)phenyl)-3-(2-(4-((5

fluoro-1,4,5,6-tetrahydropyrimidin-2-yl)amino)-lH

indazole-6-carboxamido)acetamido)propanoate

trifluoroacetate synthesized in Example 8-(a) in

acetonitrile (1 ml) and water (1 ml), 34 mg of lithium

hydroxide was added at room temperature under a stream of

argon, and the mixture was stirred at room temperature

for 30 minutes.

After the completion of reaction, the reaction

mixture was adjusted to pH 5.5 by the addition of 1 N

hydrochloric acid, and the mixture was stirred at room

temperature for 19 hours. A deposited solid was

collected by filtration, washed with water, and then

dried under reduced pressure at 600C to obtain 45 mg of

the title compound as a white solid.

221102_G2572WO English Translation (Final) clean copy

Mass spectrum (ESI, m/z): 616 [M+H]+.

'H-NMR spectrum (400MHz, CD 30D) 6: 8.48 (d, J = 2.4

Hz, 1H), 8.12 - 8.06 (m, 2H), 8.04 - 8.00 (m, 1H), 8.00

7.95 (m, 1H), 7.73 (d, J = 1.6 Hz, 1H), 7.66 - 7.62 (m,

1H), 7.54 (d, J = 1.0 Hz, 1H), 6.56 - 6.52 (m, 1H), 5.39

- 5.34 (m, 1H), 5.29 - 5.10 (m, 1H), 4.20 - 4.05 (m, 2H),

3.72 - 3.40 (m, 4H), 2.84 - 2.66 (m, 2H).

[0351] Example 9-(b)

Production of (3S)-3-(2-(4-((5-fluoro-1,4,5,6

tetrahydropyrimidin-2-yl)amino)-1H-indazole-6

carboxamido)acetamido)-3-(2-fluoro-3

(trifluoromethyl)phenyl)propanoic acid

H H O H N N N CO2H F Ni NN H 0 FFO2

N-NH CF 3

[0352] To a suspension of 88 mg of methyl (3S)-3-(2-(4

((5-fluoro-1,4,5,6-tetrahydropyrimidin-2-yl)amino)-1H

indazole-6-carboxamido)acetamido)-3-(2-fluoro-3

(trifluoromethyl)phenyl)propanoate trifluoroacetate

synthesized in Example 9-(a) in acetonitrile (1 ml) and

water (1 ml), 16 mg of lithium hydroxide was added at

room temperature under a stream of argon, and the mixture

was stirred at room temperature for 1.5 hours.

After the completion of reaction, the reaction

mixture was filtered. The filtrate was adjusted to pH

5.4 by the addition of 1 N hydrochloric acid, and the

221102_G2572WO English Translation (Final) clean copy

mixture was stirred at room temperature for 7.5 hours. A

deposited solid was collected by filtration, washed with

water, and then dried under reduced pressure at 60°C to

obtain 46 mg of the title compound as a white solid.

Mass spectrum (ESI, m/z): 568 [M+H]+.

'H-NMR spectrum (400MHz, CD 30D) 6: 8.11 (d, J = 1.0

Hz, 1H), 8.08 - 8.06 (m, 1H), 7.74 - 7.69 (m, 1H), 7.56

7.51 (m, 2H), 7.27 - 7.22 (m, 1H), 5.49 (t, J = 5.2 Hz,

1H), 5.30 - 5.13 (m, 1H), 4.16 (d, J = 16.8 Hz, 1H), 4.05

(d, J = 16.8 Hz, 1H), 3.70 - 3.45 (m, 4H), 2.76 - 2.58

(m, 2H).

[0353] Example 10-(b)

Production of (3S)-3-(2-chloro-3

(trifluoromethyl)phenyl)-3-(2-(4-((5-fluoro-1,4,5,6

tetrahydropyrimidin-2-yl)amino)-1H-indazole-6

carboxamido)acetamido)propanoic acid

H H 0 H N N N CO 2 H H Cl F N N-NH CF 3

[0354] To a suspension of 79 mg of methyl (3S)-3-(2

chloro-3-(trifluoromethyl)phenyl)-3-(2-(4-((5-fluoro

1,4,5,6-tetrahydropyrimidin-2-yl)amino)-1H-indazole-6

carboxamido)acetamido)propanoate trifluoroacetate

synthesized in Example 10-(a) in acetonitrile (1 ml) and

water (1 ml), 14 mg of lithium hydroxide was added at

221102_G2572WO English Translation (Final) clean copy

room temperature under a stream of argon, and the mixture

was stirred at room temperature for 1.5 hours.

After the completion of reaction, the reaction

mixture was filtered. The filtrate was adjusted to pH

5.4 by the addition of 1 N hydrochloric acid, and the

mixture was stirred at room temperature for 3 hours. A

deposited solid was collected by filtration, washed with

water, and then dried under reduced pressure at 600C to

obtain 58 mg of the title compound as a white solid.

Mass spectrum (ESI, m/z): 584 [M+H]+.

'H-NMR spectrum (400MHz, CD 30D) 6: 8.11 (d, J = 0.9

Hz, 1H), 8.10 - 8.07 (m, 1H), 7.77 - 7.73 (m, 1H), 7.66

7.62 (m, 1H), 7.56 (d, J = 1.3 Hz, 1H), 7.42 - 7.36 (m,

1H), 5.61 (t, J = 5.1 Hz, 1H), 5.29 - 5.13 (m, 1H), 4.17

- 4.03 (m, 2H), 3.70 - 3.45 (m, 4H), 2.75 - 2.58 (m, 2H).

[0355]

Example 11-(b)

Production of (3S)-3-(2-(4-((5-fluoro-1,4,5,6

tetrahydropyrimidin-2-yl)amino)-1H-indazole-6

carboxamido)acetamido)-3-(2-fluoro-5

(trifluoromethyl)phenyl)propanoic acid

H H 0 H NN N N CO2 H 0 F F N N-NH F3 C

[0356] To a solution of 85 mg of methyl (3S)-3-(2-(4-((5

fluoro-1,4,5,6-tetrahydropyrimidin-2-yl)amino)-1H

221102_G2572WO English Translation (Final) clean copy

indazole-6-carboxamido)acetamido)-3-(2-fluoro-5

(trifluoromethyl)phenyl)propanoate trifluoroacetate

synthesized in Example 11-(a) in acetonitrile (1 ml) and

water (1 ml), 15 mg of lithium hydroxide was added at

room temperature under a stream of argon, and the mixture

was stirred at room temperature for 3.5 hours.

After the completion of reaction, the reaction

mixture was filtered. The filtrate was adjusted to pH

5.5 by the addition of 1 N hydrochloric acid, and the

mixture was stirred at room temperature for 18 hours. A

deposited solid was collected by filtration, washed with

water, and then dried under reduced pressure at 600C to

obtain 23 mg of the title compound as a pale yellow

solid.

Mass spectrum (ESI, m/z): 568 [M+H]+.

'H-NMR spectrum (400MHz, CD 3 0D) 6: 8.10 - 8.06 (m,

2H), 7.80 - 7.76 (m, 1H), 7.61 - 7.55 (m, 1H), 7.52 (d, J

= 1.0 Hz, 1H), 7.29 - 7.23 (m, 1H), 5.50 (t, J = 5.4 Hz,

1H), 5.30 - 5.14 (m, 1H), 4.16 (d, J = 16.8 Hz, 1H), 4.06

(d, J = 16.8 Hz, 1H), 3.71 - 3.45 (m, 4H), 2.78 - 2.61

(m, 2H).

[0357] Example 12-(b)

Production of (3S)-3-(2-chloro-5

(trifluoromethyl)phenyl)-3-(2-(4-((5-fluoro-1,4,5,6

tetrahydropyrimidin-2-yl)amino)-1H-indazole-6

carboxamido)acetamido)propanoic acid

221102_G2572WO English Translation (Final) clean copy

H H H N N N N CO 2H F N 0 N Cl

N-NH F 3C

[0358] To a solution of 127 mg of methyl (3S)-3-(2

chloro-5-(trifluoromethyl)phenyl)-3-(2-(4-((5-fluoro

1,4,5,6-tetrahydropyrimidin-2-yl)amino)-lH-indazole-6

carboxamido)acetamido)propanoate trifluoroacetate

synthesized in Example 12-(a) in acetonitrile (1 ml) and

water (1 ml), 22 mg of lithium hydroxide was added at

room temperature under a stream of argon, and the mixture

was stirred at room temperature for 1 hour.

After the completion of reaction, the reaction

mixture was filtered. The filtrate was adjusted to pH

5.3 by the addition of 1 N hydrochloric acid, and the

mixture was stirred at room temperature for 16 hours. A

deposited solid was collected by filtration, washed with

water, and then dried under reduced pressure at 600C to

obtain 58 mg of the title compound as a gray solid.

Mass spectrum (ESI, m/z): 584 [M+H]+.

'H-NMR spectrum (400MHz, CD 30D) 6: 8.12 - 8.06 (m,

2H), 7.80 (d, J = 1.6 Hz, 1H), 7.59 - 7.50 (m, 3H), 5.58

(t, J = 5.3 Hz, 1H), 5.30 - 5.14 (m, 1H), 4.16 (d, J =

16.8 Hz, 1H), 4.07 (d, J= 16.8 Hz, 1H), 3.72 - 3.45 (m,

4H), 2.76 - 2.62 (m, 2H).

[0359] Example 13-(b)

221102_G2572WO English Translation (Final) clean copy

Production of (3S)-3-(2-(4-((5-fluoro-1,4,5,6

tetrahydropyrimidin-2-yl)amino)-lH-indazole-6

carboxamido)acetamido)-3-(4-fluoro-3

(trifluoromethyl)phenyl)propanoic acid

H H 0 H N N N OH N H O

N-NH CF 3 F

[0360] To a solution of 114 mg of methyl (3S)-3-(2-(4

((5-fluoro-1,4,5,6-tetrahydropyrimidin-2-yl)amino)-1H

indazole-6-carboxamido)acetamido)-3-(4-fluoro-3

(trifluoromethyl)phenyl)propanoate trifluoroacetate

synthesized in Example 1-(a) in acetonitrile (1 ml) and

water (1 ml), 20 mg of lithium hydroxide was added at

room temperature under a stream of argon, and the mixture

was stirred at room temperature for 1 hour.

After the completion of reaction, the reaction

mixture was filtered. The filtrate was adjusted to pH

5.3 by the addition of 1 N hydrochloric acid, and the

mixture was stirred at room temperature for 4 hours. A

deposited solid was collected by filtration, washed with

water, and then dried under reduced pressure at 60°C to

obtain 62 mg of the title compound as a pale yellow

solid.

Mass spectrum (ESI, m/z): 568 [M+H]+.

'H-NMR spectrum (400MHz, CD 30D) 6: 8.10 - 8.05 (m,

2H), 7.72 - 7.64 (m, 2H), 7.51 (d, J = 1.1 Hz, 1H), 7.26

221102_G2572WO English Translation (Final) clean copy

- 7.20 (m, 1H), 5.31 - 5.14 (m, 2H), 4.17 - 4.02 (m, 2H),

3.73 - 3.46 (m, 4H), 2.73 - 2.60 (m, 2H).

[0361] Example 14-(b)

Production of (3S)-3-(2-(4-((5-fluoro-1,4,5,6

tetrahydropyrimidin-2-yl)amino)-lH-indazole-6

carboxamido)acetamido)-3-(4-methyl-3

(trifluoromethyl)phenyl)propanoic acid

H H O H N N N N OH N 0 0 F'U N-NH CF 3

[0362] To a solution of 115 mg of methyl (3S)-3-(2-(4

((5-fluoro-1,4,5,6-tetrahydropyrimidin-2-yl)amino)-1H

indazole-6-carboxamido)acetamido)-3-(4-methyl-3

(trifluoromethyl)phenyl)propanoate trifluoroacetate

synthesized in Example 14-(a) in acetonitrile (1 ml) and

water (1 ml), 20 mg of lithium hydroxide was added at

room temperature under a stream of argon, and the mixture

was stirred at room temperature for 1 hour.

After the completion of reaction, the reaction

mixture was filtered. The filtrate was adjusted to pH

5.4 by the addition of 1 N hydrochloric acid, and the

mixture was stirred at room temperature for 3 hours. A

deposited solid was collected by filtration, washed with

water, and then dried under reduced pressure at 600C to

obtain 46 mg of the title compound as a white solid.

Mass spectrum (ESI, m/z): 564 [M+H]+.

221102_G2572WO English Translation (Final) clean copy

'H-NMR spectrum (400MHz, CD 30D) 6: 8.09 - 8.03 (m,

2H), 7.66 - 7.62 (m, 1H), 7.51 - 7.46 (m, 2H), 7.26 (d, J

= 8.0 Hz, 1H), 5.28 - 5.12 (m, 2H), 4.16 (d, J = 16.8 Hz,

1H), 4.05 (d, J = 16.8 Hz, 1H), 3.71 - 3.43 (m, 4H), 2.72

- 2.59 (m, 2H), 2.43 - 2.38 (m, 3H).

[0363] Example 15-(b)

Production of (3S)-3-(3-chloro-4-fluoro-5

(trifluoromethyl)phenyl)-3-(2-(4-((5-fluoro-1,4,5,6

tetrahydropyrimidin-2-yl)amino)-1H-indazole-6

carboxamido)acetamido)propanoic acid

H H 0 H N N N OH

F N F H 0~~ 0 N-NH C I CF3 F

[0364] To a solution of 90 mg of methyl (3S)-3-(3-chloro

4-fluoro-5-(trifluoromethyl)phenyl)-3-(2-(4-((5-fluoro

1,4,5,6-tetrahydropyrimidin-2-yl)amino)-lH-indazole-6

carboxamido)acetamido)propanoate trifluoroacetate

synthesized in Example 15-(a) in acetonitrile (1 ml) and

water (1 ml), 15 mg of lithium hydroxide was added at

room temperature under a stream of argon, and the mixture

was stirred at room temperature for 1 hour.

After the completion of reaction, 1 ml of water was

added to the reaction mixture, and the mixture was

filtered. The filtrate was adjusted to pH 5.5 by the

addition of 1 N hydrochloric acid. 1 ml of water and 1

ml of acetonitrile were added thereto, and the mixture

221102_G2572WO English Translation (Final) clean copy

was stirred at room temperature for 10 minutes. A

deposited solid was collected by filtration, washed with

water, and then dried under reduced pressure at 60°C to

obtain 51 mg of the title compound as a white solid.

Mass spectrum (ESI, m/z): 602 [M+H]+.

'H-NMR spectrum (400MHz, CD 30D) 6: 8.11 - 8.07 (m,

2H), 7.80 (dd, J = 2.2, 6.6 Hz, 1H), 7.66 (dd, J = 2.2,

6.0 Hz, 1H), 7.52 (d, J = 1.1 Hz, 1H), 5.30 - 5.16 (m,

2H), 4.17 - 4.02 (m, 2H), 3.73 - 3.46 (m, 4H), 2.74

2.60 (m, 2H).

[0365] Example 16-(b)

Production of (3S)-3-(3-bromo-4-methoxyphenyl)-3-(2-(4

((5-fluoro-1,4,5,6-tetrahydropyrimidin-2-yl)amino)-1H

indazole-6-carboxamido)acetamido)propanoic acid

H H H N N N N OH F N 0 0

N-NH Br

[0366] To a solution of 110 mg of methyl (3S)-3-(3-bromo

4-methoxyphenyl)-3-(2-(4-((5-fluoro-1,4,5,6

tetrahydropyrimidin-2-yl)amino)-1H-indazole-6

carboxamido)acetamido)propanoate trifluoroacetate

synthesized in Example 16-(a) in acetonitrile (1 ml) and

water (1 ml), 19 mg of lithium hydroxide was added at

room temperature under a stream of argon, and the mixture

was stirred at room temperature for 1.5 hours.

221102_G2572WO English Translation (Final) clean copy

After the completion of reaction, the reaction

mixture was filtered. The filtrate was adjusted to pH

5.2 by the addition of 1 N hydrochloric acid, and the

mixture was stirred at room temperature for 16 hours. A

deposited solid was collected by filtration, washed with

water, and then dried under reduced pressure at 600C to

obtain 62 mg of the title compound as a white solid.

Mass spectrum (ESI, m/z): 590, 592 [M+H]+.

'H-NMR spectrum (400MHz, CD 30D) 6: 8.06 - 8.01 (m,

2H), 7.55 (d, J = 2.1 Hz, 1H), 7.45 (d, J= 1.1 Hz, 1H),

7.30 (dd, J = 2.1, 8.7 Hz, 1H), 6.90 (d, J= 8.7 Hz, 1H),

5.29 - 5.11 (m, 2H), 4.16 (d, J = 16.8 Hz, 1H), 4.05 (d,

J = 16.8 Hz, 1H), 3.80 (s, 3H), 3.67 - 3.42 (m, 4H), 2.70

- 2.57 (m, 2H).

[0367] Example 17-(b)

Production of (3S)-3-(3,5-dichlorophenyl)-3-(2-(4-((5

fluoro-1,4,5,6-tetrahydropyrimidin-2-yl)amino)-1H

indazole-6-carboxamido)acetamido)propanoic acid

H H O H N N N N OH

1N H 0

N-NH CI CI

[0368] To a suspension of 120 mg of methyl (3S)-3-(3,5

dichlorophenyl)-3-(2-(4-((5-fluoro-1,4,5,6

tetrahydropyrimidin-2-yl)amino)-1H-indazole-6

carboxamido)acetamido)propanoate trifluoroacetate

synthesized in Example 17-(a) in acetonitrile (1 ml) and

221102_G2572WO English Translation (Final) clean copy

water (1 ml), 22 mg of lithium hydroxide was added at

room temperature under a stream of argon, and the mixture

was stirred at room temperature for 3.5 hours.

After the completion of reaction, the reaction

mixture was adjusted to pH 5.3 by the addition of 1 N

hydrochloric acid, and the mixture was stirred at room

temperature for 2.5 hours. A deposited solid was

collected by filtration, washed with water, and then

dried under reduced pressure at 600C to obtain 76 mg of

the title compound as a pale yellow solid.

Mass spectrum (ESI, m/z): 550 [M+H]+.

'H-NMR spectrum (400MHz, CD 30D) 6: 8.08 - 8.05 (m,

2H), 7.51 - 7.47 (m, 1H), 7.37 - 7.34 (m, 2H), 7.25 (t, J

= 1.9 Hz, 1H), 5.30 - 5.13 (m, 2H), 4.17 - 4.05 (m, 2H),

3.71 - 3.44 (m, 4H), 2.70 - 2.57 (m, 2H).

[0369] Example 18-(b)

Production of (3S)-3-(3-bromo-5-chlorophenyl)-3-(2-(4

((5-fluoro-1,4,5,6-tetrahydropyrimidin-2-yl)amino)-1H

indazole-6-carboxamido)acetamido)propanoic acid

H H 0 H N N N OH ,UN F N H F N-NH Br Cl

[0370] To a solution of 125 mg of methyl (3S)-3-(3-bromo

-chlorophenyl)-3-(2-(4-((5-fluoro-1,4,5,6

tetrahydropyrimidin-2-yl)amino)-lH-indazole-6

carboxamido)acetamido)propanoate trifluoroacetate

221102_G2572WO English Translation (Final) clean copy

synthesized in Example 18-(a) in acetonitrile (1 ml) and

water (1 ml), 21 mg of lithium hydroxide was added at

room temperature under a stream of argon, and the mixture

was stirred at room temperature for 2.5 hours.

After the completion of reaction, 2 ml of water and

0.5 ml of acetonitrile were added to the reaction

mixture, and the mixture was filtered. The filtrate was

adjusted to pH 5.8 by the addition of 1 N hydrochloric

acid, and the mixture was stirred at room temperature for

22 hours. A deposited solid was collected by filtration,

washed with water, and then dried under reduced pressure

at 600C to obtain 85 mg of the title compound as a white

solid.

Mass spectrum (ESI, m/z): 594, 596 [M+H]+.

'H-NMR spectrum (400MHz, CD 30D) 6: 8.08 - 8.05 (m,

2H), 7.52 - 7.48 (m, 2H), 7.41 - 7.38 (m, 2H), 5.30

5.13 (m, 2H), 4.17 - 4.05 (m, 2H), 3.71 - 3.45 (m, 4H),

2.70 - 2.56 (m, 2H).

[0371] Example 19-(b)

Production of (3S)-3-(3,5-dibromophenyl)-3-(2-(4-((5

fluoro-1,4,5,6-tetrahydropyrimidin-2-yl)amino)-1H

indazole-6-carboxamido)acetamido)propanoic acid

H H O H N N N N CO 2H

F N 0 N-NH Br Br

221102_G2572WO English Translation (Final) clean copy

[0372] To a suspension of 48 mg of methyl (3S)-3-(3,5

dibromophenyl)-3-(2-(4-((5-fluoro-1,4,5,6

tetrahydropyrimidin-2-yl)amino)-1H-indazole-6

carboxamido)acetamido)propanoate trifluoroacetate

synthesized in Example 19-(a) in acetonitrile (0.5 ml)

and water (0.5 ml), 13 mg of lithium hydroxide

monohydrate was added at room temperature under a stream

of argon, and the mixture was stirred at room temperature

for 1 hour.

After the completion of reaction, the reaction

mixture was adjusted to pH 5.9 by the addition of 1 M

hydrochloric acid, and the mixture was stirred overnight

at room temperature. A deposited solid was collected by

filtration, washed with water, and then dried under

reduced pressure at 500C to obtain 34 mg of the title

compound as a white solid.

Mass spectrum (ESI, m/z): 640 [M+H]+.

'H-NMR spectrum (400MHz, CD 3 0D) 6: 8.10 - 8.07 (m,

2H), 7.56 - 7.53 (m, 3H), 7.52 (d, J = 1.1 Hz, 1H), 5.31

- 5.10 (m, 2H), 4.18 - 4.03 (m, 2H), 3.71 - 3.45 (m, 4H),

2.71 - 2.54 (m, 2H).

[0373] Example 20-(b)

Production of (3S)-3-(3-bromo-5-iodophenyl)-3-(2-(4-((5

fluoro-1,4,5,6-tetrahydropyrimidin-2-yl)amino)-1H

indazole-6-carboxamido)acetamido)propanoic acid

221102_G2572WO English Translation (Final) clean copy

H H H N N N OH FN H F N-NH Br 1

[0374] To a suspension of 140 mg of methyl (3S)-3-(3

bromo-5-iodophenyl)-3-(2-(4-((5-fluoro-1,4,5,6

tetrahydropyrimidin-2-yl)amino)-lH-indazole-6

carboxamido)acetamido)propanoate trifluoroacetate

synthesized in Example 20-(a) in acetonitrile (1 ml) and

water (1 ml), 21 mg of lithium hydroxide was added at

room temperature under a stream of argon, and the mixture

was stirred at room temperature for 3.5 hours.

After the completion of reaction, the reaction

mixture was adjusted to pH 5.5 by the addition of 1 N

hydrochloric acid, and the mixture was stirred at room

temperature for 16 hours. A deposited solid was

collected by filtration, washed with water, and then

dried under reduced pressure at 60°C to obtain 88 mg of

the title compound as a light brown solid.

Mass spectrum (ESI, m/z): 686, 688 [M+H]+.

'H-NMR spectrum (400MHz, CD 30D) 6: 8.11 - 8.05 (m,

2H), 7.74 - 7.70 (m, 2H), 7.57 - 7.54 (m, 1H), 7.52 (d, J

= 1.1 Hz, 1H), 5.33 - 5.15 (m, 1H), 5.13 (t, J = 5.3 Hz,

1H), 4.17 - 4.04 (m, 2H), 3.72 - 3.45 (m, 4H), 2.69

2.55 (m, 2H).

[0375] Example 21-(b)

221102_G2572WO English Translation (Final) clean copy

Production of (3S)-3-(3-chloro-5-iodophenyl)-3-(2-(4-((5

fluoro-1,4,5,6-tetrahydropyrimidin-2-yl)amino)-1H

indazole-6-carboxamido)acetamido)propanoic acid

H H O H N N N CO 2H

F N H N-NH CI 1

[0376] To a suspension of 48 mg of methyl (3S)-3-(3

chloro-5-iodophenyl)-3-(2-(4-((5-fluoro-1,4,5,6

tetrahydropyrimidin-2-yl)amino)-lH-indazole-6

carboxamido)acetamido)propanoate trifluoroacetate

synthesized in Example 21-(a) in acetonitrile (0.5 ml)

and water (0.5 ml), 13 mg of lithium hydroxide

monohydrate was added at room temperature under a stream

of argon, and the mixture was stirred at room temperature

for 1 hour.

After the completion of reaction, the reaction

mixture was adjusted to pH 5.9 by the addition of 1 M

hydrochloric acid, and the mixture was stirred overnight

at room temperature. A deposited solid was collected by

filtration, washed with water, and then dried under

reduced pressure at 50°C to obtain 38 mg of the title

compound as a white solid.

Mass spectrum (ESI, m/z): 642 [M+H]+.

'H-NMR spectrum (400MHz, CD 30D) 6: 8.13 - 8.05 (m,

2H), 7.71 - 7.65 (m, 1H), 7.61 - 7.56 (m, 1H), 7.53 (d, J

= 1.1 Hz, 1H), 7.44 - 7.39 (m, 1H), 5.31 - 5.11 (m, 2H),

221102_G2572WO English Translation (Final) clean copy

4.18 - 4.03 (m, 2H), 3.73 - 3.45 (m, 4H), 2.71 - 2.54 (m,

2H).

[0377] Example 22-(b)

Production of (3S)-3-(5-chloro-2-fluorophenyl)-3-(2-(4

((5-fluoro-1,4,5,6-tetrahydropyrimidin-2-yl)amino)-lH

indazole-6-carboxamido)acetamido)propanoic acid

H H 0 H N N N CO2H 0 F N N-NH C1

[0378] To a solution of 203 mg of methyl (3S)-3-(5

chloro-2-fluorophenyl)-3-(2-(4-((5-fluoro-1,4,5,6

tetrahydropyrimidin-2-yl)amino)-lH-indazole-6

carboxamido)acetamido)propanoate trifluoroacetate

synthesized in Example 22-(a) in acetonitrile (1 ml) and

water (1 ml), 49 mg of lithium hydroxide was added at

room temperature under a stream of argon, and the mixture

was stirred at room temperature for 30 minutes.

After the completion of reaction, the reaction

mixture was adjusted to pH 5.5 by the addition of 1 N

hydrochloric acid, and the mixture was stirred at room

temperature for 19 hours. A deposited solid was

collected by filtration. Acetonitrile/methanol = 1/9

(v/v) (0.74 ml) was added to the obtained solid, and the

mixture was stirred at 800C. Acetonitrile/methanol = 1/9

(v/v) (0.74 ml) was further added thereto, and the

mixture was stirred at room temperature for 30 minutes.

221102_G2572WO English Translation (Final) clean copy

A deposited solid was collected by filtration, washed

with water, and then dried under reduced pressure at 600C

to obtain 46 mg of the title compound as a white solid.

Mass spectrum (ESI, m/z): 534 [M+H]+.

'H-NMR spectrum (400MHz, CD 30D) 6: 8.09 - 8.04 (m,

2H), 7.51 (d, J = 1.0 Hz, 1H), 7.44 (dd, J = 2.7, 6.5 Hz,

1H), 7.22 (ddd, J = 2.7, 4.3, 8.8 Hz, 1H), 7.05 (dd, J=

8.8, 9.9 Hz, 1H), 5.45 - 5.40 (m, 1H), 5.28 - 5.10 (m,

1H), 4.19 - 4.05 (m, 2H), 3.71 - 3.41 (m, 4H), 2.75

2.57 (m, 2H).

[0379] Example 23-(b)

Production of (3S)-3-(5-bromo-2-fluorophenyl)-3-(2-(4

((5-fluoro-1,4,5,6-tetrahydropyrimidin-2-yl)amino)-1H

indazole-6-carboxamido)acetamido)propanoic acid

H H O H N N N CO2H N H F

N-NH Br

[0380] To a solution of 145 mg of methyl (3S)-3-(5-bromo

2-fluorophenyl)-3-(2-(4-((5-fluoro-1,4,5,6

tetrahydropyrimidin-2-yl)amino)-1H-indazole-6

carboxamido)acetamido)propanoate trifluoroacetate

synthesized in Example 23-(a) in acetonitrile (1 ml) and

water (1 ml), 48 mg of lithium hydroxide was added at

room temperature under a stream of argon, and the mixture

was stirred at room temperature for 30 minutes.

221102_G2572WO English Translation (Final) clean copy

After the completion of reaction, the reaction

mixture was adjusted to pH 5.5 by the addition of 1 N

hydrochloric acid, and the mixture was stirred at room

temperature for 19 hours. A deposited solid was

collected by filtration, washed with water, and then

dried under reduced pressure at 600C to obtain 50 mg of

the title compound as a white solid.

Mass spectrum (ESI, m/z): 578, 580 [M+H]+.

'H-NMR spectrum (400MHz, CD 30D) 6: 8.11 - 8.06 (m,

2H), 7.58 (dd, J= 2.6, 6.7 Hz, 1H), 7.54 (d, J = 1.1 Hz,

1H), 7.37 (ddd, J= 2.6, 4.5, 8.7 Hz, 1H), 7.00 (dd, J=

8.7, 10.1 Hz, 1H), 5.45 - 5.40 (m, 1H), 5.30 - 5.11 (m,

1H), 4.18 - 4.05 (m, 2H), 3.73 - 3.43 (m, 4H), 2.76

2.57 (m, 2H).

[0381] Example 24-(b)

Production of (3S)-3-(3-(difluoromethoxy)-5

(trifluoromethyl)phenyl)-3-(2-(4-((5-fluoro-1,4,5,6

tetrahydropyrimidin-2-yl)amino)-1H-indazole-6

carboxamido)acetamido)propanoic acid

H H 0 H N N N CO2H N H F N -N F -F

N-NH F 0 CF 3

[0382] To a solution of 118 mg of methyl (3S)-3-(3

(difluoromethoxy)-5-(trifluoromethyl)phenyl)-3-(2-(4-((5

fluoro-1,4,5,6-tetrahydropyrimidin-2-yl)amino)-1H

indazole-6-carboxamido)acetamido)propanoate

221102_G2572WO English Translation (Final) clean copy

trifluoroacetate synthesized in Example 24-(a) in

acetonitrile (1 ml) and water (1 ml), 19 mg of lithium

hydroxide was added at room temperature under a stream of

argon, and the mixture was stirred at room temperature

for 2 hours.

After the completion of reaction, the reaction

mixture was filtered. The filtrate was adjusted to pH

5.5 by the addition of 1 N hydrochloric acid, and the

mixture was stirred at room temperature for 15 hours. A

deposited solid was collected by filtration, washed with

water, and then dried under reduced pressure at 60°C to

obtain 77 mg of the title compound as a white solid.

Mass spectrum (ESI, m/z): 616 [M+H]+.

'H-NMR spectrum (400MHz, CD 30D) 6: 8.10 - 8.05 (m,

2H), 7.59 - 7.56 (m, 1H), 7.51 (d, J = 0.9 Hz, 1H), 7.46

- 7.42 (m, 1H), 7.27 - 7.24 (m, 1H), 6.97 (t, J = 73.5

Hz, 1H), 5.32 - 5.11 (m, 2H), 4.15 (d, J = 16.8 Hz, 1H),

4.06 (d, J = 16.8 Hz, 1H), 3.71 - 3.42 (m, 4H), 2.75

2.60 (m, 2H).

[0383] Example 25-(b)

Production of (3S)-3-(3-chloro-5

(difluoromethoxy)phenyl)-3-(2-(4-((5-fluoro-1,4,5,6

tetrahydropyrimidin-2-yl)amino)-1H-indazole-6

carboxamido)acetamido)propanoic acid

H H O H N N N CO 2 H

F N /O F N-NH Cl O F

221102_G2572WO English Translation (Final) clean copy

[0384] To a solution of 135 mg of methyl (3S)-3-(3

chloro-5-(difluoromethoxy)phenyl)-3-(2-(4-((5-fluoro

1,4,5,6-tetrahydropyrimidin-2-yl)amino)-1H-indazole-6

carboxamido)acetamido)propanoate trifluoroacetate

synthesized in Example 25-(a) in acetonitrile (1 ml) and

water (1 ml), 23 mg of lithium hydroxide was added at

room temperature under a stream of argon, and the mixture

was stirred at room temperature for 1 hour.

After the completion of reaction, the reaction

mixture was filtered. The filtrate was adjusted to pH

5.5 by the addition of 1 N hydrochloric acid, and the

mixture was stirred at room temperature for 15 hours. A

deposited solid was collected by filtration, washed with

water, and then dried under reduced pressure at 600C to

obtain 55 mg of the title compound as a pale yellow

solid.

Mass spectrum (ESI, m/z): 582 [M+H]+.

'H-NMR spectrum (400MHz, CD 3 0D) 6: 8.11 - 8.06 (m,

2H), 7.51 (d, J = 1.1 Hz, 1H), 7.30 - 7.27 (m, 1H), 7.14

- 7.10 (m, 1H), 7.06 - 7.04 (m, 1H), 6.90 (t, J = 73.5

Hz, 1H), 5.32 - 5.13 (m, 2H), 4.15 - 4.06 (m, 2H), 3.74

3.45 (m, 4H), 2.78 - 2.70 (m, 2H).

[0385] Example 26-(b)

Production of (3S)-3-(3-bromo-5-(difluoromethoxy)phenyl)

3-(2-(4-((5-fluoro-1,4,5,6-tetrahydropyrimidin-2

yl)amino)-1H-indazole-6-carboxamido)acetamido)propanoic

acid

221102_G2572WO English Translation (Final) clean copy

H H 0 H N N N CO 2H

F N 0 F N-INH NH Br Br 0) O F

[0386] To a solution of 177 mg of methyl (3S)-3-(3-bromo

-(difluoromethoxy)phenyl)-3-(2-(4-((5-fluoro-1,4,5,6

tetrahydropyrimidin-2-yl)amino)-1H-indazole-6

carboxamido)acetamido)propanoate trifluoroacetate

synthesized in Example 26-(a) in acetonitrile (1 ml) and

water (1 ml), 25 mg of lithium hydroxide was added at

room temperature under a stream of argon, and the mixture

was stirred at room temperature for 30 minutes.

After the completion of reaction, the reaction

mixture was adjusted to pH 5.5 by the addition of 1 N

hydrochloric acid, and the mixture was stirred at room

temperature for 19 hours. A deposited solid was

collected by filtration, washed with water, and then

dried under reduced pressure at 600C to obtain 88 mg of

the title compound as a light brown solid.

Mass spectrum (ESI, m/z): 626, 628 [M+H]+.

'H-NMR spectrum (400MHz, CD 30D) 6: 8.11 - 8.05 (m,

2H), 7.52 (d, J = 1.1 Hz, 1H), 7.45 - 7.41 (m, 1H), 7.20

- 7.14 (m, 2H), 6.90 (t, J = 73.5 Hz, 1H), 5.32 - 5.15

(m, 2H), 4.16 - 4.04 (m, 2H), 3.73 - 3.44 (m, 4H), 2.76

2.61 (m, 2H).

[0387] Example 27-(b)

Production of (3S)-3-(3-(difluoromethoxy)-4

fluorophenyl)-3-(2-(4-((5-fluoro-1,4,5,6

221102_G2572WO English Translation (Final) clean copy

tetrahydropyrimidin-2-yl)amino)-lH-indazole-6

carboxamido)acetamido)propanoic acid

H H H N N N CO 2H Yl H F N O / F

N-NH 0 F F

[0388] To a solution of 150 mg of methyl (3S)-3-(3

(difluoromethoxy)-4-fluorophenyl)-3-(2-(4-((5-fluoro

1,4,5,6-tetrahydropyrimidin-2-yl)amino)-lH-indazole-6

carboxamido)acetamido)propanoate trifluoroacetate

synthesized in Example 27-(a) in acetonitrile (1 ml) and

water (1 ml), 49 mg of lithium hydroxide was added at

room temperature under a stream of argon, and the mixture

was stirred at room temperature for 30 minutes.

After the completion of reaction, the reaction

mixture was adjusted to pH 5.5 by the addition of 1 N

hydrochloric acid, and the mixture was stirred at room

temperature for 19 hours. A deposited solid was

collected by filtration, washed with water, and then

dried under reduced pressure at 600C to obtain 40 mg of

the title compound as a white solid.

Mass spectrum (ESI, m/z): 566 [M+H]+.

'H-NMR spectrum (400MHz, CD 30D) 6: 8.11 - 8.04 (m,

2H), 7.51 (d, J = 1.1 Hz, 1H), 7.31 (dd, J = 2.1, 7.4 Hz,

1H), 7.25 (ddd, J = 2.1, 4.4, 8.6 Hz, 1H), 7.14 (dd, J =

8.6, 10.4 Hz, 1H), 6.86 (t, J= 73.8 Hz, 1H), 5.30 - 5.14

221102_G2572WO English Translation (Final) clean copy

(m, 2H), 4.14 (d, J = 16.8 Hz, 1H), 4.04 (d, J= 16.8 Hz,

1H), 3.73 - 3.42 (m, 4H), 2.72 - 2.58 (m, 2H).

[0389] Example 28-(b)

Production of (3S)-3-(5-(difluoromethoxy)-2

fluorophenyl)-3-(2-(4-((5-fluoro-1,4,5,6

tetrahydropyrimidin-2-yl)amino)-lH-indazole-6

carboxamido)acetamido)propanoic acid

H H O H N N N CO2H F N~ H FO 0 IFFO IF F N-NH F 0

[0390] To a solution of 152 mg of methyl (3S)-3-(5

(difluoromethoxy)-2-fluorophenyl)-3-(2-(4-((5-fluoro

1,4,5,6-tetrahydropyrimidin-2-yl)amino)-lH-indazole-6

carboxamido)acetamido)propanoate trifluoroacetate

synthesized in Example 28-(a) in acetonitrile (1 ml) and

water (1 ml), 49 mg of lithium hydroxide was added at

room temperature under a stream of argon, and the mixture

was stirred at room temperature for 30 minutes.

After the completion of reaction, the reaction

mixture was adjusted to pH 5.5 by the addition of 1 N

hydrochloric acid, and the mixture was stirred at room

temperature for 19 hours. A deposited solid was

collected by filtration, washed with water, and then

dried under reduced pressure at 600C to obtain 70 mg of

the title compound as a white solid.

Mass spectrum (ESI, m/z): 566 [M+H]+.

221102_G2572WO English Translation (Final) clean copy

'H-NMR spectrum (400MHz, CD 30D) 6: 8.11 - 8.06 (m,

2H), 7.53 (d, J = 1.1 Hz, 1H), 7.22 (dd, J= 2.9, 6.1 Hz,

1H), 7.11 - 6.98 (m, 2H), 6.81 (t, J = 74.3 Hz, 1H), 5.47

- 5.42 (m, 1H), 5.30 - 5.12 (m, 1H), 4.17 - 4.03 (m, 2H),

3.71 - 3.43 (m, 4H), 2.76 - 2.61 (m, 2H).

[0391] Example 29-(b)

Production of (3S)-3-(3-(difluoromethoxy)-5-(1H-pyrazol

1-yl)phenyl)-3-(2-(4-((5-fluoro-1,4,5,6

tetrahydropyrimidin-2-yl)amino)-1H-indazole-6

carboxamido)acetamido)propanoic acid

H H O H N N N CO 2H

F N F O N-NH F ON N'N

[0392] To a solution of 162 mg of methyl (3S)-3-(3

(difluoromethoxy)-5-(1H-pyrazol-1-yl)phenyl)-3-(2-(4-((5

fluoro-1,4,5,6-tetrahydropyrimidin-2-yl)amino)-1H

indazole-6-carboxamido)acetamido)propanoate

trifluoroacetate synthesized in Example 29-(a) in

acetonitrile (1 ml) and water (1 ml), 48 mg of lithium

hydroxide was added at room temperature under a stream of

argon, and the mixture was stirred at room temperature

for 30 minutes.

After the completion of reaction, the reaction

mixture was adjusted to pH 5.5 by the addition of 1 N

hydrochloric acid. 3 ml of water was added thereto, and

the mixture was stirred at room temperature for 15 hours.

221102_G2572WO English Translation (Final) clean copy

A deposited solid was collected by filtration, washed

with water, and then dried under reduced pressure at 600C

to obtain 65 mg of the title compound as a pale yellow

solid.

Mass spectrum (ESI, m/z): 614 [M+H]+.

'H-NMR spectrum (400MHz, CD 30D) 6: 8.38 (d, J = 2.4

Hz, 1H), 8.11 - 8.06 (m, 2H), 7.69 (d, J = 1.6 Hz, 1H),

7.62 - 7.59 (m, 1H), 7.55 (d, J = 1.0 Hz, 1H), 7.46

7.43 (m, 1H), 7.13 - 7.10 (m, 1H), 6.95 (t, J = 73.9 Hz,

1H), 6.53 - 6.49 (m, 1H), 5.30 - 5.10 (m, 2H), 4.17 (d, J

= 16.7 Hz, 1H), 4.08 (d, J = 16.7 Hz, 1H), 3.70 - 3.40

(m, 4H), 2.81 - 2.64 (m, 2H).

[0393] Example 30-(b)

Production of (3S)-3-(3,5-bis(difluoromethoxy)phenyl)-3

(2-(4-((5-fluoro-1,4,5,6-tetrahydropyrimidin-2-yl)amino)

1H-indazole-6-carboxamido)acetamido)propanoic acid

H H O H N N N N OH

N HF 0 0 FU W F 11 F N-NH F 0 0 F

[0394] To a suspension of 51 mg of methyl (3S)-3-(3,5

bis(difluoromethoxy)phenyl)-3-(2-(4-((5-fluoro-1,4,5,6

tetrahydropyrimidin-2-yl)amino)-1H-indazole-6

carboxamido)acetamido)propanoate trifluoroacetate

synthesized in Example 30-(a) in acetonitrile (0.5 ml)

and water (0.5 ml), 15 mg of lithium hydroxide

monohydrate was added at room temperature under a stream

221102_G2572WO English Translation (Final) clean copy

of argon, and the mixture was stirred at room temperature

for 1 hour.

After the completion of reaction, the reaction

mixture was adjusted to pH 5.9 by the addition of 1 M

hydrochloric acid, and the mixture was stirred overnight

at room temperature. A deposited solid was collected by

filtration, washed with water, and then dried under

reduced pressure at 500C to obtain 44 mg of the title

compound as a brown solid.

Mass spectrum (ESI, m/z): 614 [M+H]+.

'H-NMR spectrum (400MHz, CD 30D) 6: 8.10 - 8.03 (m,

2H), 7.54 - 7.48 (m, 1H), 7.06 - 7.00 (m, 2H), 6.90 (t, J

= 73.9 Hz, 2H), 6.77 - 6.74 (m, 1H), 5.30 - 5.12 (m, 2H),

4.19 - 3.99 (m, 2H), 3.72 - 3.43 (m, 4H), 2.71 - 2.57 (m,

2H).

[0395] Example 31-(b)

Production of (3S)-3-(3-chloro-5

(trifluoromethoxy)phenyl)-3-(2-(4-((5-fluoro-1,4,5,6

tetrahydropyrimidin-2-yl)amino)-lH-indazole-6

carboxamido)acetamido)propanoic acid

H H O H N N N CO 2 H N H

N--NH C1 OCF 3

[0396] To a suspension of 70 mg of methyl (3S)-3-(3

chloro-5-(trifluoromethoxy)phenyl)-3-(2-(4-((5-fluoro

1,4,5,6-tetrahydropyrimidin-2-yl)amino)-lH-indazole-6

221102_G2572WO English Translation (Final) clean copy

carboxamido)acetamido)propanoate trifluoroacetate

synthesized in Example 31-(a) in acetonitrile (0.5 ml)

and water (0.5 ml), 21 mg of lithium hydroxide

monohydrate was added at room temperature under a stream

of argon, and the mixture was stirred at room temperature

for 1 hour.

After the completion of reaction, the reaction

mixture was adjusted to pH 5.9 by the addition of 1 M

hydrochloric acid, and the mixture was stirred overnight

at room temperature. A deposited solid was collected by

filtration, washed with water, and then dried under

reduced pressure at 50°C to obtain 52 mg of the title

compound as a white solid.

Mass spectrum (ESI, m/z): 600 [M+H]+.

'H-NMR spectrum (400MHz, CD 30D) 6: 8.13 - 8.05 (m,

2H), 7.52 (d, J = 1.3 Hz, 1H), 7.46 - 7.42 (m, 1H), 7.29

- 7.25 (m, 1H), 7.21 - 7.18 (m, 1H), 5.34 -5.13 (m, 2H),

4.17 - 4.05 (m, 2H), 3.78 - 3.45 (m, 4H), 2.77 - 2.65 (m,

2H).

[0397] Example 32-(b)

Production of (3S)-3-(3-bromo-5

(trifluoromethoxy)phenyl)-3-(2-(4-((5-fluoro-1,4,5,6

tetrahydropyrimidin-2-yl)amino)-1H-indazole-6

carboxamido)acetamido)propanoic acid

H H 0 H N N N OH

F NH 0 0 F N-NH Br OCF 3

221102_G2572WO English Translation (Final) clean copy

[0398] To a solution of 321 mg of methyl (3S)-3-(3-bromo

-(trifluoromethoxy)phenyl)-3-(2-(4-((5-fluoro-1,4,5,6

tetrahydropyrimidin-2-yl)amino)-1H-indazole-6

carboxamido)acetamido)propanoate trifluoroacetate

synthesized in Example 32-(a) in acetonitrile (2.5 ml)

and water (2.5 ml), 50 mg of lithium hydroxide was added

at room temperature under a stream of argon, and the

mixture was stirred at room temperature for 3.5 hours.

After the completion of reaction, 2.5 ml of water

was added to the reaction mixture. The reaction mixture

was adjusted to pH 5.0 by the addition of 1 N

hydrochloric acid, and the mixture was stirred at room

temperature for 20 hours. A deposited solid was

collected by filtration, washed with water, and then

dried under reduced pressure at 600C to obtain 244 mg of

the title compound as a white solid.

Mass spectrum (ESI, m/z): 644, 646 [M+H]+.

'H-NMR spectrum (400MHz, CD 3 0D) 6: 8.12 - 8.06 (m,

2H), 7.61 - 7.58 (m, 1H), 7.51 (d, J = 1.1 Hz, 1H), 7.36

- 7.33 (m, 1H), 7.33 - 7.30 (m, 1H), 5.33 - 5.16 (m, 2H),

4.16 - 4.05 (m, 2H), 3.73 - 3.49 (m, 4H), 2.76 (d, J =

6.4 Hz, 2H).

[0399] Example 33-(b)

Production of (3S)-3-(2-(4-((5-fluoro-1,4,5,6

tetrahydropyrimidin-2-yl)amino)-1H-indazole-6

carboxamido)acetamido)-3-(2-fluoro-5

(trifluoromethoxy)phenyl)propanoic acid

221102_G2572WO English Translation (Final) clean copy

H H 0 H N N N CO2H F N N F C 2 N HH 0 IF N-NH F3CO

[0400] To a solution of 270 mg of methyl (3S)-3-(2-(4

((5-fluoro-1,4,5,6-tetrahydropyrimidin-2-yl)amino)-1H

indazole-6-carboxamido)acetamido)-3-(2-fluoro-5

(trifluoromethoxy)phenyl)propanoate trifluoroacetate

synthesized in Example 33-(a) in acetonitrile (2 ml) and

water (2 ml), 45 mg of lithium hydroxide was added at

room temperature under a stream of argon, and the mixture

was stirred at room temperature for 1 hour.

After the completion of reaction, the reaction

mixture was adjusted to pH 5.2 by the addition of 1 N

hydrochloric acid. 4 ml of water was added thereto, and

the mixture was stirred at room temperature for 16 hours.

A deposited solid was collected by filtration, washed

with water, and then dried under reduced pressure at 600C

to obtain 169 mg of the title compound as a white solid.

Mass spectrum (ESI, m/z): 584 [M+H]+.

'H-NMR spectrum (400MHz, CD 30D) 6: 8.08 - 8.05 (m,

2H), 7.50 - 7.48 (m, 1H), 7.38 - 7.34 (m, 1H), 7.20

7.12 (m, 2H), 5.49 - 5.44 (m, 1H), 5.30 - 5.14 (m, 1H),

4.18 - 4.04 (m, 2H), 3.73 - 3.41 (m, 4H), 2.78 - 2.61 (m,

2H).

[0401] Example 34-(b)

221102_G2572WO English Translation (Final) clean copy

Production of (3S)-3-(2-(4-((5-fluoro-1,4,5,6

tetrahydropyrimidin-2-yl)amino)-lH-indazole-6

carboxamido)acetamido)-3-(4-fluoro-3

(trifluoromethoxy)phenyl)propanoic acid

H H O H N N N N OH N OH 0

N--NH OCF3 F

[0402] To a solution of 93 mg of methyl (3S)-3-(2-(4-((5

fluoro-1,4,5,6-tetrahydropyrimidin-2-yl)amino)-lH

indazole-6-carboxamido)acetamido)-3-(4-fluoro-3

(trifluoromethoxy)phenyl)propanoate trifluoroacetate

synthesized in Example 34-(a) in acetonitrile (1 ml) and

water (1 ml), 16 mg of lithium hydroxide was added at

room temperature under a stream of argon, and the mixture

was stirred at room temperature for 2.5 hours.

After the completion of reaction, 1 ml of water was

added to the reaction mixture, and the mixture was

filtered. The filtrate was adjusted to pH 5.6 by the

addition of 1 N hydrochloric acid, and the mixture was

stirred at room temperature for 18 hours. A deposited

solid was collected by filtration, washed with water, and

then dried under reduced pressure at 600C to obtain 63 mg

of the title compound as a white solid.

Mass spectrum (ESI, m/z): 584 [M+H]+.

'H-NMR spectrum (400MHz, CD 30D) 6: 8.08 (d, J = 1.0

Hz, 1H), 8.07 - 8.05 (m, 1H), 7.50 (d, J = 1.1 Hz, 1H),

221102_G2572WO English Translation (Final) clean copy

7.46 - 7.37 (m, 2H), 7.22 (dd, J= 8.6, 10.1 Hz, 1H),

5.31 - 5.14 (m, 2H), 4.15 (d, J= 16.8 Hz, 1H), 4.05 (d,

J = 16.8 Hz, 1H), 3.72 - 3.46 (m, 4H), 2.71 - 2.58 (m,

2H).

[0403] Example 35-(b)

Production of (3S)-3-(2-(4-((5-fluoro-1,4,5,6

tetrahydropyrimidin-2-yl)amino)-1H-indazole-6

carboxamido)acetamido)-3-(3

(trifluoromethyl)phenyl)propanoic acid

H H 0 H N N N N OH F N H 0 0

N-NH I CF 3

[0404] To a solution of 142 mg of methyl (3S)-3-(2-(4

((5-fluoro-1,4,5,6-tetrahydropyrimidin-2-yl)amino)-1H

indazole-6-carboxamido)acetamido)-3-(3

(trifluoromethyl)phenyl)propanoate trifluoroacetate

synthesized in Example 35-(a) in acetonitrile (1.5 ml)

and water (1.5 ml), 26 mg of lithium hydroxide was added

at room temperature under a stream of argon, and the

mixture was stirred at room temperature for 1 hour.

After the completion of reaction, the reaction

mixture was filtered. The filtrate was adjusted to pH

5.4 by the addition of 1 N hydrochloric acid, and the

mixture was stirred at room temperature for 16 hours.

The reaction mixture was concentrated under reduced

pressure, and acetonitrile was distilled off under

221102_G2572WO English Translation (Final) clean copy

reduced pressure. The residue was stirred at room

temperature for 3 hours. A deposited solid was collected

by filtration, washed with water, and then dried under

reduced pressure at 600C to obtain 63 mg of the title

compound as a pale yellow solid.

Mass spectrum (ESI, m/z): 550 [M+H]+.

'H-NMR spectrum (400MHz, CD 30D) 6: 8.10 - 8.04 (m,

2H), 7.73 - 7.67 (m, 1H), 7.67 - 7.61 (m, 1H), 7.53

7.45 (m, 3H), 5.31 (t, J = 5.5 Hz, 1H), 5.29 - 5.13 (m,

1H), 4.20 - 4.04 (m, 2H), 3.72 - 3.44 (m, 4H), 2.77

2.64 (m, 2H).

[0405] Example 36-(b)

Production of (3S)-3-(2-(4-((5-fluoro-1,4,5,6

tetrahydropyrimidin-2-yl)amino)-lH-indazole-6

carboxamido)acetamido)-3-(3

(trifluoromethoxy)phenyl)propanoic acid

H H O H N N NyN -- OH

N OH 0

N-NH OCF 3

[0406] To a solution of 104 mg of methyl (3S)-3-(2-(4

((5-fluoro-1,4,5,6-tetrahydropyrimidin-2-yl)amino)-1H

indazole-6-carboxamido)acetamido)-3-(3

(trifluoromethoxy)phenyl)propanoate trifluoroacetate

synthesized in Example 36-(a) in acetonitrile (1 ml) and

water (1 ml), 18 mg of lithium hydroxide was added at

221102_G2572WO English Translation (Final) clean copy

room temperature under a stream of argon, and the mixture

was stirred at room temperature for 1 hour.

After the completion of reaction, the reaction

mixture was filtered. The filtrate was adjusted to pH

5.2 by the addition of 1 N hydrochloric acid. The

reaction mixture was concentrated under reduced pressure,

and acetonitrile was distilled off under reduced

pressure. The residue was stirred at room temperature

for 2 hours. A deposited solid was collected by

filtration, washed with water, and then dried under

reduced pressure at 60°C to obtain 50 mg of the title

compound as a pale yellow solid.

Mass spectrum (ESI, m/z): 566 [M+H]+.

'H-NMR spectrum (400MHz, CD 30D) 6: 8.08 (d, J = 0.9

Hz, 1H), 8.06 - 8.04 (m, 1H), 7.48 (d, J = 1.1 Hz, 1H),

7.41 - 7.36 (m, 2H), 7.32 - 7.28 (m, 1H), 7.15 - 7.09 (m,

1H), 5.33 - 5.14 (m, 2H), 4.18 - 4.04 (m, 2H), 3.71

3.45 (m, 4H), 2.78 - 2.66 (m, 2H).

[0407] Example 37-(b)

Production of (3S)-3-(3-(difluoromethoxy)phenyl)-3-(2-(4

((5-fluoro-1,4,5,6-tetrahydropyrimidin-2-yl)amino)-1H

indazole-6-carboxamido)acetamido)propanoic acid

H H O H N N N N OH

F N O OF N-NH 0 F

221102_G2572WO English Translation (Final) clean copy

[0408] To a solution of 110 mg of methyl (3S)-3-(3

(difluoromethoxy)phenyl)-3-(2-(4-((5-fluoro-1,4,5,6

tetrahydropyrimidin-2-yl)amino)-1H-indazole-6

carboxamido)acetamido)propanoate trifluoroacetate

synthesized in Example 37-(a) in acetonitrile (1 ml) and

water (1 ml), 20 mg of lithium hydroxide was added at

room temperature under a stream of argon, and the mixture

was stirred at room temperature for 1 hour.

After the completion of reaction, the reaction

mixture was filtered. The filtrate was adjusted to pH

5.5 by the addition of 1 N hydrochloric acid. The

reaction mixture was concentrated under reduced pressure,

and acetonitrile was distilled off under reduced

pressure. The residue was stirred at room temperature

for 2.5 hours. A deposited solid was collected by

filtration, washed with water, and then dried under

reduced pressure at 600C to obtain 50 mg of the title

compound as a beige solid.

Mass spectrum (ESI, m/z): 548 [M+H]+.

'H-NMR spectrum (400MHz, CD 3 0D) 6: 8.10 - 8.03 (m,

2H), 7.50 (d, J = 1.1 Hz, 1H), 7.32 - 7.27 (m, 1H), 7.26

- 7.21 (m, 1H), 7.18 - 7.15 (m, 1H), 6.98 - 6.93 (m, 1H),

6.83 (t, J = 74.3 Hz, 1H), 5.29 - 5.12 (m, 2H), 4.19

4.02 (m, 2H), 3.70 - 3.43 (m, 4H), 2.72 - 2.60 (m, 2H).

[0409] Example 38-(b)

221102_G2572WO English Translation (Final) clean copy

Production of (3S)-3-(3-(difluoromethyl)phenyl)-3-(2-(4

((5-fluoro-1,4,5,6-tetrahydropyrimidin-2-yl)amino)-1H

indazole-6-carboxamido)acetamido)propanoic acid

H H 0 H N N N N OH

F N O O N-NH F F

[0410] To a solution of 150 mg of methyl (3S)-3-(3

(difluoromethyl)phenyl)-3-(2-(4-((5-fluoro-1,4,5,6

tetrahydropyrimidin-2-yl)amino)-lH-indazole-6

carboxamido)acetamido)propanoate trifluoroacetate

synthesized in Example 38-(a) in acetonitrile (1 ml) and

water (1 ml), 28 mg of lithium hydroxide was added at

room temperature under a stream of argon, and the mixture

was stirred at room temperature for 2.5 hours.

After the completion of reaction, the reaction

mixture was filtered. The filtrate was adjusted to pH

5.3 by the addition of 1 N hydrochloric acid, and the

mixture was stirred at room temperature for 18 hours. A

deposited solid was collected by filtration, washed with

water, and then dried under reduced pressure at 60°C to

obtain 60 mg of the title compound as a white solid.

Mass spectrum (ESI, m/z): 532 [M+H]+.

'H-NMR spectrum (400MHz, CD 30D) 6: 8.06 (d, J = 1.0

Hz, 1H), 8.05 - 8.02 (m, 1H), 7.57 - 7.51 (m, 2H), 7.47

(d, J = 1.3 Hz, 1H), 7.42 - 7.35 (m, 2H), 6.71 (t, J =

56.2 Hz, 1H), 5.30 - 5.11 (m, 2H), 4.17 (d, J = 16.8 Hz,

221102_G2572WO English Translation (Final) clean copy

1H), 4.06 (d, J = 16.8 Hz, 1H), 3.68 - 3.41 (m, 4H), 2.75

- 2.63 (m, 2H).

[0411] Example 39-(b)

Production of (3S)-3-(3-cyclopropylphenyl)-3-(2-(4-((5

fluoro-1,4,5,6-tetrahydropyrimidin-2-yl)amino)-lH

indazole-6-carboxamido)acetamido)propanoic acid

H H 0 H N N N CO 2H N H

N-NH

[0412] To a solution of 149 mg of methyl (3S)-3-(3

cyclopropylphenyl)-3-(2-(4-((5-fluoro-1,4,5,6

tetrahydropyrimidin-2-yl)amino)-lH-indazole-6

carboxamido)acetamido)propanoate trifluoroacetate

synthesized in Example 39-(a) in acetonitrile (1 ml) and

water (1 ml), 25 mg of lithium hydroxide was added at

room temperature under a stream of argon, and the mixture

was stirred at room temperature for 30 minutes.

After the completion of reaction, the reaction

mixture was adjusted to pH 5.5 by the addition of 1 N

hydrochloric acid, and the mixture was stirred at room

temperature for 19 hours. A deposited solid was

collected by filtration, washed with water, and then

dried under reduced pressure at 600C to obtain 66 mg of

the title compound as a white solid.

Mass spectrum (ESI, m/z): 522 [M+H]+.

221102_G2572WO English Translation (Final) clean copy

'H-NMR spectrum (400MHz, CD 30D) 6: 8.06 (d, J = 1.0

Hz, 1H), 8.03 (dd, J = 1.0, 1.1 Hz, 1H), 7.47 (d, J = 1.1

Hz, 1H), 7.14 - 7.07 (m, 3H), 6.89 - 6.85 (m, 1H), 5.27

5.11 (m, 2H), 4.19 (d, J = 16.7 Hz, 1H), 4.03 (d, J =

16.7 Hz, 1H), 3.70 - 3.38 (m, 4H), 2.71 - 2.58 (m, 2H),

1.88 - 1.79 (m, 1H), 0.93 - 0.83 (m, 2H), 0.70 - 0.59 (m,

2H).

[0413] Example 40-(b)

Production of (3S)-3-(3-cyclopropoxyphenyl)-3-(2-(4-((5

fluoro-1,4,5,6-tetrahydropyrimidin-2-yl)amino)-1H

indazole-6-carboxamido)acetamido)propanoic acid

H H H N N N CO2H

F N N-NH O

[0414] To a solution of 155 mg of methyl (3S)-3-(3

cyclopropoxyphenyl)-3-(2-(4-((5-fluoro-1,4,5,6

tetrahydropyrimidin-2-yl)amino)-1H-indazole-6

carboxamido)acetamido)propanoate trifluoroacetate

synthesized in Example 40-(a) in acetonitrile (1 ml) and

water (1 ml), 25 mg of lithium hydroxide was added at

room temperature under a stream of argon, and the mixture

was stirred at room temperature for 30 minutes.

After the completion of reaction, the reaction

mixture was adjusted to pH 5.5 by the addition of 1 N

hydrochloric acid, and the mixture was stirred at room

temperature for 15 hours. A deposited solid was

collected by filtration, washed with water, and then

221102_G2572WO English Translation (Final) clean copy

dried under reduced pressure at 600C to obtain 51 mg of

the title compound as a white solid.

Mass spectrum (ESI, m/z): 538 [M+H]+.

'H-NMR spectrum (400MHz, CD 30D) 6: 8.06 (d, J = 0.9

Hz, 1H), 8.02 (dd, J = 0.9, 1.1 Hz, 1H), 7.45 (d, J= 1.1

Hz, 1H), 7.16 (dd, J = 7.7, 7.8 Hz, 1H), 7.06 (dd, J=

1.9, 2.1 Hz, 1H), 6.98 - 6.94 (m, 1H), 6.87 (dd, J = 2.1,

7.8 Hz, 1H), 5.27 - 5.11 (m, 2H), 4.19 (d, J = 16.8 Hz,

1H), 4.04 (d, J = 16.8 Hz, 1H), 3.73 (tt, J = 3.0, 6.0

Hz, 1H), 3.68 - 3.40 (m, 4H), 2.72 - 2.60 (m, 2H), 0.79

0.55 (m, 4H).

[0415] Example 41-(b)

Production of (3S)-3-(3-chlorophenyl)-3-(2-(4-((5-fluoro

1,4,5,6-tetrahydropyrimidin-2-yl)amino)-1H-indazole-6

carboxamido)acetamido)propanoic acid

H H O H N N N N OH F IN O O

N-NH C1

[0416] To a solution of 99 mg of methyl (3S)-3-(3

chlorophenyl)-3-(2-(4-((5-fluoro-1,4,5,6

tetrahydropyrimidin-2-yl)amino)-1H-indazole-6

carboxamido)acetamido)propanoate trifluoroacetate

synthesized in Example 41-(a) in acetonitrile (1 ml) and

water (1 ml), 19 mg of lithium hydroxide was added at

room temperature under a stream of argon, and the mixture

was stirred at room temperature for 4 hours.

221102_G2572WO English Translation (Final) clean copy

After the completion of reaction, 1 ml of water was

added to the reaction mixture, and the mixture was

filtered. The filtrate was adjusted to pH 5.4 by the

addition of 1 N hydrochloric acid, and the mixture was

stirred at room temperature for 4 hours. A deposited

solid was collected by filtration, washed with water, and

then dried under reduced pressure at 600C to obtain 33 mg

of the title compound as a white solid.

Mass spectrum (ESI, m/z): 516 [M+H]+.

'H-NMR spectrum (400MHz, CD 30D) 6: 8.08 (d, J = 1.0

Hz, 1H), 8.07 - 8.06 (m, 1H), 7.50 (d, J = 1.3 Hz, 1H),

7.42 - 7.39 (m, 1H), 7.32 - 7.28 (m, 1H), 7.25 (t, J =

7.7 Hz, 1H), 7.21 - 7.17 (m, 1H), 5.29 - 5.13 (m, 2H),

4.18 - 4.04 (m, 2H), 3.71 - 3.44 (m, 4H), 2.71 - 2.59 (m,

2H).

[0417] Example 42-(b)

Production of (3S)-3-(3-bromophenyl)-3-(2-(4-((5-fluoro

1,4,5,6-tetrahydropyrimidin-2-yl)amino)-1H-indazole-6

carboxamido)acetamido)propanoic acid

H H 0 H N N N OH F H 0 0 F N--NH Br

[0418] To a suspension of 122 mg of methyl (3S)-3-(3

bromophenyl)-3-(2-(4-((5-fluoro-1,4,5,6

tetrahydropyrimidin-2-yl)amino)-1H-indazole-6

carboxamido)acetamido)propanoate trifluoroacetate

221102_G2572WO English Translation (Final) clean copy

synthesized in Example 42-(a) in acetonitrile (1 ml) and

water (1 ml), 22 mg of lithium hydroxide was added at

room temperature under a stream of argon, and the mixture

was stirred at room temperature for 2 hours.

After the completion of reaction, 1 ml of water was

added to the reaction mixture, and the mixture was

filtered. The filtrate was adjusted to pH 5.3 by the

addition of 1 N hydrochloric acid, and the mixture was

stirred at room temperature for 2 hours. A deposited

solid was collected by filtration, washed with water, and

then dried under reduced pressure at 600C to obtain 66 mg

of the title compound as a white solid.

Mass spectrum (ESI, m/z): 560, 562 [M+H]+.

'H-NMR spectrum (400MHz, CD 30D) 6: 8.09 - 8.06 (m,

2H), 7.56 (t, J = 1.7 Hz, 1H), 7.52 (d, J = 1.1 Hz, 1H),

7.36 - 7.32 (m, 2H), 7.22 - 7.17 (m, 1H), 5.30 - 5.14 (m,

2H), 4.18 - 4.04 (m, 2H), 3.71 - 3.45 (m, 4H), 2.70

2.57 (m, 2H).

[0419] Example 43-(b)

Production of (3S)-3-(3-(1H-pyrazol-1-yl)phenyl)-3-(2-(4

((5-fluoro-1,4,5,6-tetrahydropyrimidin-2-yl)amino)-1H

indazole-6-carboxamido)acetamido)propanoic acid

H H H N N N N CO 2H

F F N O N--NH -N N2

221102_G2572WO English Translation (Final) clean copy

[0420] To a solution of 123 mg of methyl (3S)-3-(3-(1H

pyrazol-1-yl)phenyl)-3-(2-(4-((5-fluoro-1,4,5,6

tetrahydropyrimidin-2-yl)amino)-1H-indazole-6

carboxamido)acetamido)propanoate trifluoroacetate

synthesized in Example 43-(a) in acetonitrile (1 ml) and

water (1 ml), 25 mg of lithium hydroxide was added at

room temperature under a stream of argon, and the mixture

was stirred at room temperature for 30 minutes.

After the completion of reaction, the reaction

mixture was adjusted to pH 5.5 by the addition of 1 N

hydrochloric acid, and the mixture was stirred at room

temperature for 19 hours. The reaction mixture was

purified by BondElut (eluting solvent:

water:acetonitrile:methanol) to obtain 49 mg of the title

compound as a white solid.

Mass spectrum (ESI, m/z): 548 [M+H]+.

'H-NMR spectrum (400MHz, CD 3 0D) 6: 8.30 (dd, J = 0.5,

2.5 Hz, 1H), 8.08 (d, J = 0.8 Hz, 1H), 8.06 (dd, J = 0.8,

1.3 Hz, 1H), 7.74 - 7.70 (m, 1H), 7.68 - 7.67 (m, 1H),

7.61 - 7.55 (m, 1H), 7.52 (d, J = 1.3 Hz, 1H), 7.44

7.31 (m, 2H), 6.49 (dd, J = 1.9, 2.5 Hz, 1H), 5.33 - 5.28

(m, 1H), 5.25 - 5.07 (m, 1H), 4.21 - 4.06 (m, 2H), 3.66

3.37 (m, 4H), 2.84 - 2.65 (m, 2H).

[0421] Example 44-(b)

Production of (3S)-3-(3-(3,5-dimethyl-1H-pyrazol-1

yl)phenyl)-3-(2-(4-((5-fluoro-1,4,5,6

221102_G2572WO English Translation (Final) clean copy

tetrahydropyrimidin-2-yl)amino)-lH-indazole-6

carboxamido)acetamido)propanoic acid

H H 0 H N N N CO 2 H

F N H N-NH N

[0422] To a solution of 120 mg of methyl (3S)-3-(3-(3,5

dimethyl-1H-pyrazol-1-yl)phenyl)-3-(2-(4-((5-fluoro

1,4,5,6-tetrahydropyrimidin-2-yl)amino)-lH-indazole-6

carboxamido)acetamido)propanoate trifluoroacetate

synthesized in Example 44-(a) in acetonitrile (1 ml) and

water (1 ml), 41 mg of lithium hydroxide was added at

room temperature under a stream of argon, and the mixture

was stirred at room temperature for 1 hour.

After the completion of reaction, the reaction

mixture was adjusted to pH 5.0 by the addition of 1 N

hydrochloric acid, and the mixture was stirred at room

temperature for 1 hour.

The reaction mixture was concentrated under reduced

pressure, and acetonitrile was distilled off under

reduced pressure. 300 ptl of acetonitrile was added to

the residue, and the mixture was stirred at room

temperature for 1 hour. A deposited solid was collected

by filtration, washed with water, and then dried under

reduced pressure at 600C to obtain 35 mg of the title

compound as a white solid.

Mass spectrum (ESI, m/z): 576 [M+H]+.

221102_G2572WO English Translation (Final) clean copy

'H-NMR spectrum (400MHz, CD 30D) 6: 8.03 (d, J = 0.9

Hz, 1H), 8.00 - 7.98 (m, 1H), 7.47 - 7.39 (m, 4H), 7.29

7.22 (m, 1H), 6.00 (s, 1H), 5.33 - 5.28 (m, 1H), 5.26

5.08 (m, 1H), 4.17 (d, J = 16.8 Hz, 1H), 4.06 (d, J =

16.8 Hz, 1H), 3.66 - 3.38 (m, 4H), 2.82 - 2.60 (m, 2H),

2.23 (s, 3H), 2.19 (s, 3H).

[0423] Example 45-(b)

Production of (3S)-3-(2-(4-((5-fluoro-1,4,5,6

tetrahydropyrimidin-2-yl)amino)-1H-indazole-6

carboxamido)acetamido)-3-(3-morpholinophenyl)propanoic

acid

H H 0 H N N N CO2H

F N O N--NH N O

[0424] To a solution of 78 mg of methyl (3S)-3-(2-(4-((5

fluoro-1,4,5,6-tetrahydropyrimidin-2-yl)amino)-1H

indazole-6-carboxamido)acetamido)-3-(3

morpholinophenyl)propanoate trifluoroacetate synthesized

in Example 45-(a) in acetonitrile (1 ml) and water (1

ml), 27 mg of lithium hydroxide was added at room

temperature under a stream of argon, and the mixture was

stirred at room temperature for 30 minutes.

After the completion of reaction, the reaction

mixture was adjusted to pH 5.5 by the addition of 1 N

hydrochloric acid, and the mixture was stirred at room

temperature for 19 hours. The reaction mixture was

221102_G2572WO English Translation (Final) clean copy

purified by BondElut (eluting solvent:

water:acetonitrile:methanol) to obtain 44 mg of the title

compound as a white solid.

Mass spectrum (ESI, m/z): 567 [M+H]+.

'H-NMR spectrum (400MHz, CD 30D) 6: 8.08 (d, J = 0.9

Hz, 1H), 8.03 (dd, J = 0.9, 1.1 Hz, 1H), 7.48 (d, J = 1.1

Hz, 1H), 7.18 - 7.12 (m, 1H), 6.99 - 6.96 (m, 1H), 6.89

6.85 (m, 1H), 6.80 - 6.76 (m, 1H), 5.28 - 5.11 (m, 2H),

4.20 (d, J = 16.7 Hz, 1H), 4.01 (d, J = 16.7 Hz, 1H),

3.80 - 3.74 (m, 4H), 3.69 - 3.39 (m, 4H), 3.14 - 3.06 (m,

4H), 2.79 - 2.57 (m, 2H).

[0425] Example 46-(b)

Production of (3S)-3-(4-(difluoromethoxy)phenyl)-3-(2-(4

((5-fluoro-1,4,5,6-tetrahydropyrimidin-2-yl)amino)-1H

indazole-6-carboxamido)acetamido)propanoic acid

H H 0 H

F N N 0 OH N-NH

O F F

[0426] To a solution of 126 mg of methyl (3S)-3-(4

(difluoromethoxy)phenyl)-3-(2-(4-((5-fluoro-1,4,5,6

tetrahydropyrimidin-2-yl)amino)-1H-indazole-6

carboxamido)acetamido)propanoate trifluoroacetate

synthesized in Example 46-(a) in acetonitrile (1 ml) and

water (1 ml), 23 mg of lithium hydroxide was added at

room temperature under a stream of argon, and the mixture

was stirred at room temperature for 1 hour.

221102_G2572WO English Translation (Final) clean copy

After the completion of reaction, 1 ml of water was

added to the reaction mixture, and the mixture was

filtered. The filtrate was adjusted to pH 5.5 by the

addition of 1 N hydrochloric acid, and the mixture was

stirred at room temperature for 17 hours. A deposited

solid was collected by filtration, washed with water, and

then dried under reduced pressure at 600C to obtain 69 mg

of the title compound as a white solid.

Mass spectrum (ESI, m/z): 548 [M+H]+.

'H-NMR spectrum (400MHz, CD 30D) 6: 8.09 (d, J= 1.0

Hz, 1H), 8.06 - 8.04 (m, 1H), 7.50 (d, J = 1.3 Hz, 1H),

7.42 - 7.38 (m, 2H), 7.06 - 7.02 (m, 2H), 6.73 (t, J =

74.3 Hz, 1H), 5.28 - 5.13 (m, 2H), 4.19 - 4.01 (m, 2H),

3.70 - 3.42 (m, 4H), 2.71 - 2.59 (m, 2H).

[0427] Example 47-(b)

Production of (3S)-3-(2-(4-((5-fluoro-1,4,5,6

tetrahydropyrimidin-2-yl)amino)-1H-indazole-6

carboxamido)acetamido)-3-(4

(trifluoromethyl)phenyl)propanoic acid

H H 0 H N N N N OH

N N-NH CF 3

[0428] To a solution of 125 mg of methyl (3S)-3-(2-(4

((5-fluoro-1,4,5,6-tetrahydropyrimidin-2-yl)amino)-1H

indazole-6-carboxamido)acetamido)-3-(4

(trifluoromethyl)phenyl)propanoate trifluoroacetate

221102_G2572WO English Translation (Final) clean copy

synthesized in Example 47-(a) in acetonitrile (1 ml) and

water (1 ml), 23 mg of lithium hydroxide was added at

room temperature under a stream of argon, and the mixture

was stirred at room temperature for 2.5 hours.

After the completion of reaction, 1 ml of water was

added to the reaction mixture, and the mixture was

filtered. The filtrate was adjusted to pH 5.4 by the

addition of 1 N hydrochloric acid, and the mixture was

stirred at room temperature for 4 hours. A deposited

solid was collected by filtration, washed with water, and

then dried under reduced pressure at 600C to obtain 70 mg

of the title compound as a white solid.

Mass spectrum (ESI, m/z): 550 [M+H]+.

'H-NMR spectrum (400MHz, CD 30D) 6: 8.09 (d, J = 1.0

Hz, 1H), 8.07 - 8.05 (m, 1H), 7.56 (s, 4H), 7.52 (d, J=

1.1 Hz, 1H), 5.30 - 5.13 (m, 2H), 4.17 (d, J = 16.8 Hz,

1H), 4.07 (d, J = 16.8 Hz, 1H), 3.71 - 3.43 (m, 4H), 2.74

- 2.62 (m, 2H).

[0429] Example 48-(b)

Production of (3S)-3-(3-chloro-5

(trifluoromethyl)phenyl)-3-(2-(3-fluoro-4-((5-fluoro

1,4,5,6-tetrahydropyrimidin-2-yl)amino)-1H-indazole-6

carboxamido)acetamido)propanoic acid F

H

FH i FC,

221102_G2572WO English Translation (Final) clean copy

[0430] To a solution of 65 mg of methyl (3S)-3-(3-chloro

-(trifluoromethyl)phenyl)-3-(2-(3-fluoro-4-((5-fluoro

1,4,5,6-tetrahydropyrimidin-2-yl)amino)-1H-indazole-6

carboxamido)acetamido)propanoate trifluoroacetate

synthesized in Example 48-(a) in acetonitrile (0.8 ml)

and water (0.8 ml), 10 mg of lithium hydroxide was added

at room temperature under a stream of argon, and the

mixture was stirred at room temperature for 30 minutes.

Subsequently, 10 mg of lithium hydroxide was further

added thereto at room temperature, and the mixture was

stirred at room temperature for 30 minutes.

After the completion of reaction, the reaction

mixture was adjusted to pH 5.6 by the addition of 1 N

hydrochloric acid. 1.6 ml of water was added thereto,

and the mixture was stirred at room temperature for 16

hours. A deposited solid was collected by filtration,

washed with water, and then dried under reduced pressure

at 600C to obtain 38 mg of the title compound as a white

solid.

Mass spectrum (ESI, m/z): 602 [M+H]+.

'H-NMR spectrum (400MHz, CD 3 0D) 6: 8.01 - 7.94 (m,

1H), 7.70 - 7.61 (m, 2H), 7.55 - 7.49 (m, 1H), 7.46

7.41 (m, 1H), 5.31 - 5.08 (m, 2H), 4.18 - 4.03 (m, 2H),

3.70 - 3.41 (m, 4H), 2.79 - 2.56 (m, 2H).

[0431] Example 49-(b)

Production of (3S)-3-(2-(3-chloro-4-((5-fluoro-1,4,5,6

tetrahydropyrimidin-2-yl)amino)-1H-indazole-6

221102_G2572WO English Translation (Final) clean copy

carboxamido)acetamido)-3-(3-chloro-5

(trifluoromethyl)phenyl)propanoic acid F

HN N o OH C1HN I~ N( CIH OH N-NH CI CF3

[0432] To a solution of 54 mg of methyl (3S)-3-(2-(3

chloro-4-((5-fluoro-1,4,5,6-tetrahydropyrimidin-2

yl)amino)-lH-indazole-6-carboxamido)acetamido)-3-(3

chloro-5-(trifluoromethyl)phenyl)propanoate

trifluoroacetate synthesized in Example 49-(a) in

acetonitrile (0.5 ml) and water (0.5 ml), 10 mg of

lithium hydroxide was added at room temperature under a

stream of argon, and the mixture was stirred at room

temperature for 1 hour.

After the completion of reaction, 1 ml of water was

added to the reaction mixture. The reaction mixture was

adjusted to pH 5.6 by the addition of 1 N hydrochloric

acid, and the mixture was stirred at room temperature for

22 hours. A deposited solid was collected by filtration,

washed with water, and then dried under reduced pressure

at 600C to obtain 36 mg of the title compound as a white

solid.

Mass spectrum (ESI, m/z): 618 [M+H]+.

'H-NMR spectrum (400MHz, CD 30D) 6: 8.14 (d, J = 1.3

Hz, 1H), 7.69 - 7.67 (m, 1H), 7.65 - 7.62 (m, 1H), 7.56

(d, J = 1.1 Hz, 1H), 7.54 - 7.51 (m, 1H), 5.27 - 5.10 (m,

221102_G2572WO English Translation (Final) clean copy

2H), 4.17 - 4.04 (m, 2H), 3.68 - 3.44 (m, 4H), 2.73

2.59 (m, 2H).

[0433] Example 50-(b)

Production of (3S)-3-(3-chloro-5

(trifluoromethyl)phenyl)-3-(2-(4-((5-hydroxy-1,4,5,6

tetrahydropyrimidin-2-yl)amino)-lH-indazole-6

carboxamido)acetamido)propanoic acid

H H 0 H N NN OH

NHH HOC1 CF 3 N-NH C ~

[0434] To a solution of 115 mg of methyl (3S)-3-(3

chloro-5-(trifluoromethyl)phenyl)-3-(2-(4-((5-hydroxy

1,4,5,6-tetrahydropyrimidin-2-yl)amino)-1H-indazole-6

carboxamido)acetamido)propanoate trifluoroacetate

synthesized in Example 50-(a) in acetonitrile (1 ml) and

water (1 ml), 20 mg of lithium hydroxide was added at

room temperature under a stream of argon, and the mixture

was stirred at room temperature for 1.5 hours.

After the completion of reaction, the reaction

mixture was filtered. The filtrate was adjusted to pH

5.6 by the addition of 1 N hydrochloric acid, and the

mixture was stirred at room temperature for 4 hours. A

deposited solid was collected by filtration, washed with

water, and then dried under reduced pressure at 600C to

obtain 72 mg of the title compound as a white solid.

Mass spectrum (ESI, m/z): 582 [M+H]+.

221102_G2572WO English Translation (Final) clean copy

'H-NMR spectrum (400MHz, CD 30D) 6: 8.16 (d, J = 1.0

Hz, 1H), 8.06 - 8.04 (m, 1H), 7.70 - 7.67 (m, 1H), 7.66

7.63 (m, 1H), 7.53 - 7.51 (m, 1H), 7.50 (d, J = 1.1 Hz,

1H), 5.26 (t, J = 5.3 Hz, 1H), 4.24 (quin, J = 3.1 Hz,

1H), 4.18 - 4.05 (m, 2H), 3.49 - 3.38 (m, 2H), 3.36

3.29 (m, 2H), 2.74 - 2.60 (m, 2H).

[0435] Example 51-(b)

Production of (S)-3-(3-chloro-5-(trifluoromethyl)phenyl)

3-(2-(4-((1,4,5,6-tetrahydropyrimidin-2-yl)amino)-1H

indazole-6-carboxamido)acetamido)propanoic acid

NON CH O H -N0 0 N-NH C1 Fa

[0436] To a suspension of 117 mg of methyl (S)-3-(3

chloro-5-(trifluoromethyl)phenyl)-3-(2-(4-((1,4,5,6

tetrahydropyrimidin-2-yl)amino)-1H-indazole-6

carboxamido)acetamido)propanoate trifluoroacetate

synthesized in Example 51-(a) in acetonitrile (1 ml) and

water (1 ml), 21 mg of lithium hydroxide was added at

room temperature under a stream of argon, and the mixture

was stirred at room temperature for 1 hour.

After the completion of reaction, the reaction

mixture was filtered. The filtrate was adjusted to pH

5.6 by the addition of 1 N hydrochloric acid, and the

mixture was stirred at room temperature for 2 hours. A

deposited solid was collected by filtration, washed with

221102_G2572WO English Translation (Final) clean copy

water, and then dried under reduced pressure at 600C to

obtain 47 mg of the title compound as a white solid.

Mass spectrum (ESI, m/z): 566 [M+H]+.

'H-NMR spectrum (400MHz, CD 30D) 6: 8.12 (d, J = 1.0

Hz, 1H), 8.04 - 8.02 (m, 1H), 7.71 - 7.68 (m, 1H), 7.67

7.64 (m, 1H), 7.54 - 7.51 (m, 1H), 7.49 (d, J = 1.1 Hz,

1H), 5.26 (t, J = 5.2 Hz, 1H), 4.16 (d, J = 16.8 Hz, 1H),

4.06 (d, J = 16.8 Hz, 1H), 3.40 - 3.26 (m, 4H), 2.75

2.59 (m, 2H), 2.00 - 1.90 (m, 2H).

[0437] Example 52-(b)

Production of (3S)-3-(3-chloro-5

(trifluoromethyl)phenyl)-3-(2-(6-((5-fluoro-1,4,5,6

tetrahydropyrimidin-2-yl)amino)-1H-indazole-4

carboxamido)acetamido)propanoic acid

H H 0 H N N N OH

F NN H0 0 F / O y HN-N CI CF3

[0438] To a suspension of 152 mg of methyl (3S)-3-(3

chloro-5-(trifluoromethyl)phenyl)-3-(2-(6-((5-fluoro

1,4,5,6-tetrahydropyrimidin-2-yl)amino)-1H-indazole-4

carboxamido)acetamido)propanoate trifluoroacetate

synthesized in Example 52-(a) in acetonitrile (2 ml) and

water (2 ml), 26 mg of lithium hydroxide was added at

room temperature under a stream of argon, and the mixture

was stirred at room temperature for 2 hours.

221102_G2572WO English Translation (Final) clean copy

After the completion of reaction, the reaction

mixture was filtered. The filtrate was adjusted to pH

5.8 by the addition of 1 N hydrochloric acid, and the

mixture was stirred at room temperature for 4 hours. A

deposited solid was collected by filtration, washed with

water, and then dried under reduced pressure at 600C to

obtain 86 mg of the title compound as a white solid.

Mass spectrum (ESI, m/z): 584 [M+H]+.

'H-NMR spectrum (400MHz, CD 30D) 6: 8.48 - 8.45 (m,

1H), 7.71 - 7.68 (m, 1H), 7.66 - 7.64 (m, 1H), 7.62 (d, J

= 1.6 Hz, 1H), 7.61 - 7.58 (m, 1H), 7.54 - 7.51 (m, 1H),

5.29 - 5.12 (m, 2H), 4.19 - 4.10 (m, 2H), 3.72 - 3.46 (m,

4H), 2.72 - 2.59 (m, 2H).

[0439] Example 53-(b)

Production of (3S)-3-(3-bromo-5-(trifluoromethyl)phenyl)

3-(2-(6-((5-fluoro-1,4,5,6-tetrahydropyrimidin-2

yl)amino)-1H-indazole-4-carboxamido)acetamido)propanoic

acid

H H 0 H N N N CO 2 H

F N 0 HN-N Br CF 3

[0440] To a solution of 192 mg of methyl (3S)-3-(3-bromo

-(trifluoromethyl)phenyl)-3-(2-(6-((5-fluoro-1,4,5,6

tetrahydropyrimidin-2-yl)amino)-1H-indazole-4

carboxamido)acetamido)propanoate trifluoroacetate

synthesized in Example 53-(a) in acetonitrile (3 ml) and

221102_G2572WO English Translation (Final) clean copy

water (3 ml), 30 mg of lithium hydroxide was added at

room temperature under a stream of argon, and the mixture

was stirred at room temperature for 30 minutes.

After the completion of reaction, the reaction

mixture was adjusted to pH 5.8 by the addition of 1 N

hydrochloric acid, and the mixture was stirred at room

temperature for 2 hours. A deposited solid was collected

by filtration, washed with water, and then dried under

reduced pressure at 600C to obtain 84 mg of the title

compound as a white solid.

Mass spectrum (ESI, m/z): 628, 630 [M+H]+.

'H-NMR spectrum (400MHz, DMSO-d 6 +D 20) 6: 8.35 - 8.31

(m, 1H), 7.86 - 7.83 (m, 1H), 7.79 - 7.67 (m, 2H), 7.54

7.49 (m, 1H), 7.44 - 7.40 (m, 1H), 5.32 - 5.06 (m, 2H),

4.07 - 3.89 (m, 2H), 3.60 - 3.29 (m, 4H), 2.62 - 2.40 (m,

2H).

[0441] Example 54-(b)

Production of (3S)-3-(2-(6-((5-fluoro-1,4,5,6

tetrahydropyrimidin-2-yl)amino)-lH-indazole-4

carboxamido)acetamido)-3-(3-iodo-5

(trifluoromethyl)phenyl)propanoic acid

H H 0 H N N N OH

H O F N HN-N CF3

[0442] To a solution of 85 mg of methyl (3S)-3-(2-(6-((5

fluoro-1,4,5,6-tetrahydropyrimidin-2-yl)amino)-1H

221102_G2572WO English Translation (Final) clean copy

indazole-4-carboxamido)acetamido)-3-(3-iodo-5

(trifluoromethyl)phenyl)propanoate trifluoroacetate

synthesized in Example 54-(a) in acetonitrile (1 ml) and

water (1 ml), 13 mg of lithium hydroxide was added at

room temperature under a stream of argon, and the mixture

was stirred at room temperature for 1 hour.

After the completion of reaction, the reaction

mixture was adjusted to pH 5.4 by the addition of 1 N

hydrochloric acid, and the mixture was filtered. The

filtrate was concentrated under reduced pressure, and

acetonitrile was distilled off under reduced pressure.

The residue was stirred at room temperature for 5 hours.

A deposited solid was collected by filtration, washed

with water, and then dried under reduced pressure at 600C

to obtain 38 mg of the title compound as a white solid.

Mass spectrum (ESI, m/z): 676 [M+H]+.

'H-NMR spectrum (400MHz, CD 3 0D) 6: 8.48 - 8.47 (m,

1H), 8.03 - 8.01 (m, 1H), 7.84 - 7.82 (m, 1H), 7.72

7.69 (m, 1H), 7.62 (d, J = 1.6 Hz, 1H), 7.60 - 7.58 (m,

1H), 5.27 - 5.12 (m, 2H), 4.20 - 4.08 (m, 2H), 3.72

3.46 (m, 4H), 2.71 - 2.57 (m, 2H).

[0443] Example 55-(b)

Production of (3S)-3-(2-(6-((5-fluoro-1,4,5,6

tetrahydropyrimidin-2-yl)amino)-1H-indazole-4

carboxamido)acetamido)-3-(4-fluoro-3

(trifluoromethyl)phenyl)propanoic acid

221102_G2572WO English Translation (Final) clean copy

H H 0 H N NN n N OOH

F N H0 0 HN-N CF 3 F

[0444] To a suspension of 142 mg of methyl (3S)-3-(2-(6

((5-fluoro-1,4,5,6-tetrahydropyrimidin-2-yl)amino)-1H

indazole-4-carboxamido)acetamido)-3-(4-fluoro-3

(trifluoromethyl)phenyl)propanoate trifluoroacetate

synthesized in Example 55-(a) in acetonitrile (1.5 ml)

and water (1.5 ml), 25 mg of lithium hydroxide was added

at room temperature under a stream of argon, and the

mixture was stirred at room temperature for 1.5 hours.

After the completion of reaction, the reaction

mixture was filtered. The filtrate was adjusted to pH

5.5 by the addition of 1 N hydrochloric acid, and the

mixture was stirred at room temperature for 2 hours. A

deposited solid was collected by filtration, washed with

water, and then dried under reduced pressure at 600C to

obtain 77 mg of the title compound as a white solid.

Mass spectrum (ESI, m/z): 568 [M+H]+.

'H-NMR spectrum (400MHz, CD 30D) 6: 8.45 - 8.43 (m,

1H), 7.73 - 7.64 (m, 2H), 7.62 - 7.59 (m, 2H), 7.27

7.20 (m, 1H), 5.28 - 5.13 (m, 2H), 4.20 - 4.08 (m, 2H),

3.72 - 3.46 (m, 4H), 2.71 - 2.57 (m, 2H).

[0445] Example 56-(b)

Production of (3S)-3-(2-(6-((5-fluoro-1,4,5,6

tetrahydropyrimidin-2-yl)amino)-lH-indazole-4

221102_G2572WO English Translation (Final) clean copy

carboxamido)acetamido)-3-(3

(trifluoromethyl)phenyl)propanoic acid

H H 0 H N N N N OH

O O F N HN-N CF 3

[0446] To a suspension of 161 mg of methyl (3S)-3-(2-(6

((5-fluoro-1,4,5,6-tetrahydropyrimidin-2-yl)amino)-1H

indazole-4-carboxamido)acetamido)-3-(3

(trifluoromethyl)phenyl)propanoate trifluoroacetate

synthesized in Example 56-(a) in acetonitrile (1.5 ml)

and water (1.5 ml), 28 mg of lithium hydroxide was added

at room temperature under a stream of argon, and the

mixture was stirred at room temperature for 1 hour.

After the completion of reaction, the reaction

mixture was filtered. The filtrate was adjusted to pH

5.8 by the addition of 1 N hydrochloric acid, and the

mixture was stirred at room temperature for 3 hours. A

deposited solid was collected by filtration, washed with

water, and then dried under reduced pressure at 600C to

obtain 96 mg of the title compound as a white solid.

Mass spectrum (ESI, m/z): 550 [M+H]+.

'H-NMR spectrum (400MHz, CD 30D) 6: 8.45 - 8.43 (m,

1H), 7.72 - 7.68 (m, 1H), 7.67 - 7.63 (m, 1H), 7.62 (d, J

= 1.6 Hz, 1H), 7.60 - 7.58 (m, 1H), 7.50 - 7.46 (m, 2H),

5.32 - 5.27 (m, 1H), 5.27 - 5.11 (m, 1H), 4.21 - 4.09 (m,

2H), 3.71 - 3.46 (m, 4H), 2.73 - 2.60 (m, 2H).

221102_G2572W0 English Translation (Final) clean copy

[0447] (Test Example 1) axvfl cell adhesion inhibition

test

Test Example 1 was performed by partially modifying

the method of Reed et al. (Sci Transl Med., 7 (288),

288ra79, 2015).

Human fibronectin (manufactured by Sigma-Aldrich Co.

LLC, F0895) was prepared at 1.25 pg/mL with phosphate

buffered saline (PBS), dispensed at 100 pL/well to a 96

well plate, and left standing overnight. The plate was

washed with Hanks' balanced salt solution (HBSS), then

subjected to blocking treatment with Dulbecco's modified

Eagle medium (DMEM) containing 1% bovine serum-derived

albumin (BSA) (FUJIFILM Wako Pure Chemical Corp., for

cell culture, 017-22231), and used as a coated plate in

the adhesion test.

[0448] axv-transfected cells (CHO cells deficient in u5

gene and transfected with av gene) cultured in Ham's F-12

medium (FUJIFILM Wako Pure Chemical Corp., 087-08335)

containing 10% fetal bovine serum (FBS), 1%

penicillin/streptomycin/amphotericin B (manufactured by

Thermo Fisher Scientific, Inc., 15240), 1 mM GlutaMAX

Supplement (manufactured by Thermo Fisher Scientific,

Inc., 35050), and 400 pg/mL hygromycin B (FUJIFILM Wako

Pure Chemical Corp., 080-07683) were recovered and

suspended in DMEM containing 1 mM MnCl 2 (manufactured by

Sigma-Aldrich Co. LLC, M1787) to prepare a cell

221102_G2572WO English Translation (Final) clean copy

suspension. A test compound dissolved in DMSO was added

thereto.

[0449] The cell suspension of 1 x 106 cells/mL containing

the test compound was added at 100 pL/well to the coated

plate and left standing for 1 hour in a 5% C02 incubator

(37°C) . One hour later, the supernatant was removed, and

the plate was washed with HBSS. The cells that adhered

to each well in the plate were stained with crystal

violet, and the cells were lysed, followed by absorbance

measurement. Inhibition without substrate coating was

defined as 100% inhibition, and inhibition when DMSO was

added instead of the test compound was defined as 0%

inhibition. The rate of inhibition of cell adhesion by

the test compound was calculated according to the

following expression.

Rate of inhibition of cell adhesion (%) = [1

{(Absorbance in the case of adding the test compound)

(Absorbance without substrate coating)} / {(Absorbance in

the case of adding DMSO) - (Absorbance without substrate

coating)}] x 100

[0450] An IC50 value was calculated from the rate of

inhibition of cell adhesion by the test compound. The

results about each test compound in this test are shown

in Table 18 below. A: IC50 < 3 nM, B: 3 nM < IC50 < 10 nM,

C: 10 nM < IC50 < 30 nM, D: 30 nM < IC50 < 100 nM, or E:

IC5o > 100 nM.

221102_G2572WO English Translation (Final) clean copy

Table 18. Results of avp1 cell adhesion inhibition test about compound of Example Example No. IC 50 Example No. IC 50 Example No. IC50 1-(b) A 21-(b) A 41-(b) B 2-(b) B 22-(b) C 42-(b) B 3-(b) B 23-(b) A 43-(b) B 4-(b) B 24-(b) A 44-(b) A -(b) A 25-(b) A 45-(b) A 6-(b) A 26-(b) A 46-(b) B 7-(b) A 27-(b) A 47-(b) B 8-(b) A 28-(b) A 48-(b) B 9-(b) B 29-(b) A 49-(b) A 10-(b) E 30-(b) A 50-(b) C 11-(b) B 31-(b) B 51-(b) D 12-(b) B 32-(b) A 52-(b) A 13-(b) A 33-(b) A 53-(b) A 14-(b) A 34-(b) A 54-(b) A 15-(b) A 35-(b) B 55-(b) A 16-(b) A 36-(b) B 56-(b) B 17-(b) A 37-(b) B 18-(b) A 38-(b) A 19-(b) A 39-(b) A 20-(b) A 40-(b) A

[0451] (Test Example 2) axvf6 cell adhesion inhibition

test

Test Example 2 was performed by partially modifying

the method of Henderson et al. (Nat Med., 19 (12), 1617

24, 2013). In Test Example 2, the same reagents as in

Test Example 1 were used unless otherwise specified.

Recombinant human LAP protein (manufactured by R&D

Systems, Inc., 246-LP-025) was prepared at 0.2 pg/mL with

221102_G2572WO English Translation (Final) clean copy

PBS, dispensed at 100 pL/well to a 96-well plate, and

left standing overnight. The plate was washed with HBSS,

then subjected to blocking treatment with DMEM containing

1% BSA, and used as a coated plate in the adhesion test.

[0452] HT-29 cells cultured in McCoy's 5A medium

(manufactured by Thermo Fisher Scientific, Inc., 16600)

containing 10% FBS and 1%

penicillin/streptomycin/amphotericin B were recovered and

suspended in DMEM containing 0.1% BSA and 200 pM MnCl 2 to

prepare a cell suspension. A test compound was added

thereto.

[0453] The cell suspension of 5 x 105 cells/mL containing

the test compound was added at 100 pL/well to the coated

plate and left standing for 1 hour in a 5% C02 incubator

(37°C) . One hour later, the supernatant was removed, and

the plate was washed with HBSS containing 200 pM MnCl 2 . The cells that adhered to each well in the plate were

stained with crystal violet, and the cells were lysed,

followed by absorbance measurement. Inhibition without

substrate coating was defined as 100% inhibition, and

inhibition when DMSO was added instead of the test

compound was defined as 0% inhibition. The rate of

inhibition of cell adhesion by the test compound was

calculated according to the following expression.

Rate of inhibition of cell adhesion (%) = [1

{(Absorbance in the case of adding the test compound)

(Absorbance without substrate coating)} / {(Absorbance in

221102_G2572WO English Translation (Final) clean copy

the case of adding DMSO) - (Absorbance without substrate

coating)}] x 100

[0454] An IC50 value was calculated from the rate of

inhibition of cell adhesion by the test compound. The

results about each test compound in this test are shown

in Table 19 below. A: IC50 < 3 nM, B: 3 nM < IC50 < 10 nM,

C: 10 nM < IC50 < 30 nM, D: 30 nM < IC50 < 100 nM, or E:

IC50 100 nM.

Table 19. Results of avp6 cell adhesion inhibition test about compound of Example Example No. IC50 Example No. IC50 Example No. IC 50 1-(b) A 21-(b) A 41-(b) A 2-(b) A 22-(b) B 42-(b) A 3-(b) A 23-(b) B 43-(b) A 4-(b) A 24-(b) A 44-(b) A -(b) A 25-(b) A 45-(b) B 6-(b) B 26-(b) A 46-(b) B 7-(b) A 27-(b) B 47-(b) B 8-(b) A 28-(b) A 48-(b) A 9-(b) A 29-(b) A 49-(b) A 10-(b) E 30-(b) A 50-(b) C 11-(b) A 31-(b) A 51-(b) C 12-(b) B 32-(b) A 52-(b) A 13-(b) A 33-(b) A 53-(b) A 14-(b) A 34-(b) A 54-(b) A 15-(b) A 35-(b) A 55-(b) A 16-(b) A 36-(b) A 56-(b) B 17-(b) B 37-(b) A 18-(b) A 38-(b) A 19-(b) A 39-(b) A 20-(b) A 40-(b) A

221102_G2572WO English Translation (Final) clean copy

[0455] (Test Example 3) TGF- activation inhibition test

In Test Example 3, the inhibition of TGF

activation by a compound was detected with the inhibition

of SMAD3 phosphorylation as an index. In Test Example 3,

the same reagents as in Test Example 1 were used unless

otherwise specified.

Human fibronectin was prepared at 14 pg/mL with PBS

and then dispensed at 50 pL/well to a 96-well plate. The

plate was left standing at room temperature for 1 hour or

longer, followed by the removal of the fibronectin

solution. The plate was washed with PBS and used as a

coated plate.

[0456] A test compound dissolved in DMSO was added to

RPMI medium 1640 (manufactured by Thermo Fisher

Scientific, Inc., 11875) containing 1% FBS and 1%

penicillin/streptomycin/amphotericin B to prepare a

medium containing the test compound having a

concentration of two times the final concentration. This

medium was added at 100 pL/well to the coated plate.

TFK-1 cells (Cell Resource Center for Biomedical

Research, Institute of Development, Aging and Cancer,

Tohoku University) cultured in RPMI medium 1640

containing 10% FBS and 1%

penicillin/streptomycin/amphotericin B were suspended in

RPMI medium 1640 containing 1% FBS and 1%

penicillin/streptomycin/amphotericin B to prepare a cell

suspension of 1 x 106 cells/mL. The prepared cell

221102_G2572WO English Translation (Final) clean copy

suspension was further added at 100 pL/well and cultured

for 2 days in a 5% C02 incubator (37°C).

[0457] Phosphorylated SMAD3 in the cells thus cultured

for 2 days was measured using Phospho-SMAD3 (Ser423/425)

cellular kit (manufactured by cisbio, 63ADK025), and a

DeltaF value was calculated according to the calculation

expression of the kit. Inhibition when 10 pM LY364947

(FUJIFILM Wako Pure Chemical Corp., 123-05981) was added

instead of the test compound was defined as 100%

inhibition, and inhibition when DMSO was added instead

was defined as 0% inhibition. The rate of inhibition of

phosphorylated SMAD3 by the test compound was calculated

according to the following expression.

Rate of inhibition of phosphorylated SMAD3 (%) = [1

- {(DeltaF value in the case of adding the test compound)

- (DeltaF value in the case of adding 10 pM LY364947)}

{(DeltaF value in the case of adding DMSO) - (DeltaF / value in the case of adding 10 pM LY364947)}] x 100

[0458] An IC 50 value was calculated from the rate of

inhibition of phosphorylated SMAD3 by the test compound.

The results about each test compound in this test are

shown in Table 20 below. A: IC50 < 10 nM, B: 10 nM < IC 50

< 50 nM, C: 50 nM < IC50 < 100 nM, or D: IC 50 > 100 nM.

221102_G2572WO English Translation (Final) clean copy

Table 20. Results of TGF-p activation inhibition test about compound of Example Example No. IC 50 Example No. IC 50 Example No. IC50 1-(b) A 21-(b) A 41-(b) A 2-(b) A 22-(b) B 42-(b) B 3-(b) A 23-(b) B 43-(b) A 4-(b) A 24-(b) A 44-(b) A -(b) B 25-(b) A 45-(b) B 6-(b) B 26-(b) A 46-(b) C 7-(b) A 27-(b) A 47-(b) B 8-(b) A 28-(b) B 48-(b) A 9-(b) C 29-(b) A 49-(b) A 10-(b) D 30-(b) A 50-(b) D 11-(b) A 31-(b) A 51-(b) C 12-(b) D 32-(b) A 52-(b) A 13-(b) B 33-(b) A 53-(b) A 14-(b) A 34-(b) A 54-(b) A 15-(b) A 35-(b) B 55-(b) A 16-(b) B 36-(b) B 56-(b) A 17-(b) A 37-(b) A 18-(b) B 38-(b) C 19-(b) A 39-(b) A 20-(b) A 40-(b) B

[0459] (Test Example 4) Active human hepatic stellate

cell dedifferentiation test

Human hepatic stellate cells (manufactured by

ScienCell Research Laboratories, Inc., 5300) were

suspended in DMEM containing 10% FBS and 1%

penicillin/streptomycin/amphotericin B to prepare a cell

suspension of 0.5 x 105 cells/mL, which was regarded as

cells at the start of differentiation. The cells at the

start of differentiation were dispensed at 1 mL/well to a

221102_G2572WO English Translation (Final) clean copy

12-well plate and cultured, for differentiation, for 3

days in a 5% C02 incubator (37°C).

The culture solution in each well was removed, and

DMEM containing 10% FBS and 1%

penicillin/streptomycin/amphotericin B supplemented with

a test compound dissolved in DMSO (final DMSO

concentration: 0.1%) was added at 1 mL/well. The

resultant was further cultured for 2 days in a 5% C02

incubator (37°C) . In Test Example 4, the same reagents

as in Test Example 1 were used unless otherwise

specified.

[0460] RNA in the cultured cells was extracted using

NucleoSpin(R) RNA (manufactured by Takara Bio Inc.,

U0955C), and cDNA was further synthesized from the

extracted RNA using Prime Script(TM) RT reagent Kit with

gDNA Eraser (manufactured by Takara Bio Inc., RR047A).

Real time PCR was performed using the synthesized cDNA,

various primers and TB Green(R) Premix Ex Taq(TM) II

(manufactured by Takara Bio Inc., RR820A) and using PCR

Thermal Cycler Dice Real Time (manufactured by Takara Bio

Inc., System Code TP910, Model Code TP900). The primers

used were actin alpha 2, smooth muscle (ACTA2) primer

(manufactured by Takara Bio Inc., HA136273) and

glyceraldehyde-3-phosphate dehydrogenase (GAPDH) primer

(manufactured by Takara Bio Inc., HA067812).

[0461] The amplification curve of PCR was analyzed by the

comparative Ct method. The expression level of ACTA2

221102_G2572WO English Translation (Final) clean copy

mRNA was corrected with the expression level of GAPDH

mRNA. An ACTA2 mRNA expression level when DMSO was added

instead of the test compound was defined as 100%, and an

ACTA2 mRNA expression level in the cells at the start of

differentiation was defined as 0%. The rate of decrease

in ACTA2 mRNA expression by the test compound was

calculated according to the following expression.

Rate of decrease in ACTA2 mRNA expression (%) = [1

{(ACTA2 mRNA expression level in the case of adding the

test compound) - (ACTA2 mRNA expression level in the

cells at the start of differentiation)} / {(ACTA2 mRNA

expression level in the case of adding DMSO) - (ACTA2

mRNA expression level in the cells at the start of

differentiation)}] x 100

[0462] An IC50 value was calculated from the rate of

decrease in ACTA2 mRNA expression by the test compound.

The results about each test compound in this test are

shown in Table 21 below. A: IC50 < 10 nM, B: 10 nM < IC50

< 50 nM, C: 50 nM < IC50 < 100 nM, or D: IC50 100 nM.

221102_G2572WO English Translation (Final) clean copy

Table 21. Results of active human hepatic stellate cell dedifferentiation test about compound of Example Example No. IC50 Example No. IC50 Example No. IC 50

1-(b) A 21-(b) B 41-(b) B 2-(b) B 42-(b) B 3-(b) B 43-(b) B 4-(b) B 24-(b) A -(b) A 25-(b) A 6-(b) B 26-(b) A 7-(b) A 8-(b) C 28-(b) B 48-(b) A 9-(b) B 49-(b) A 10-(b) D 30-(b) A 11-(b) A 31-(b) A 12-(b) B 32-(b) B 52-(b) B 13-(b) B 33-(b) B 53-(b) B 14-(b) A 34-(b) B 54-(b) B 15-(b) A 35-(b) A 55-(b) A 16-(b) A 36-(b) B 56-(b) A 17-(b) B 37-(b) B 18-(b) A 38-(b) A 19-(b) A 39-(b) A 20-(b) A 40-(b) B

[0463] (Test Example 5) Hepatic fibrosis suppression test

in hepatic fibrosis (non-alcoholic steatohepatitis: NASH)

model

Test Example 5 was carried out by partially

modifying the method of Matsumoto et al. (Int J Exp

Pathol., 94 (2), 93-103 (2013)).

C57BL/6J mice (male, Japan SLC, Inc.) were fed with

CDAHFD (choline-deficient amino acid-defined high fat

diet, supplemented with 0.1% methionine, 60 kcal% fat,

221102_G2572WO English Translation (Final) clean copy

manufactured by Research Diets Inc., A06071302) for 8

weeks to prepare hepatic fibrosis models. The start of

feeding with CDAHFD was defined as week 0. A test

compound or a vehicle was administered once a day during

a period from weeks 0 to 8. The group given the test

compound was used as a test compound administration

group, and the group given the vehicle was used as a

vehicle group.

Mice fed with CE-2 (CLEA Japan, Inc.) instead of

CDAHFD were used as a non-fibrotic group. Eight weeks

later, each mouse was euthanized by blood letting from

the abdomen under inhalation anesthesia with isoflurane,

and the liver was harvested.

Hydroxyproline (HYP) was quantified using a portion

of the liver, and a hepatic HYP level per unit weight was

calculated. The amount of increase in hepatic HYP level

per unit weight of the vehicle group based on the hepatic

HYP level of the non-fibrotic group was defined as 100%.

The rate of suppression of increase in HYP in the test

compound administration group was calculated.

As a result of testing compounds of Examples, the

compounds of Examples suppressed increase in HYP.

[0464] (Test Example 6) Transcellular transport test

using Caco2 cell

Caco2 cells (purchased from ATCC) were cultured in

DMEM medium (Thermo Fisher Scientific, Inc., 11965)

containing 10% FBS (Thermo Fisher Scientific, Inc.,

221102_G2572WO English Translation (Final) clean copy

10082) and 1% penicillin/streptomycin/amphotericin B

(Thermo Fisher Scientific, Inc., 15240). A transcellular

transport test was carried out in accordance with

MultiScreen Caco2 Drug Transport Assembly in a 96-well

system (Application Note AN1727EN, MultiScreen Caco-2

Assay System, Merck) by partially modifying it. The

Caco2 cells were inoculated at a cell density of 4 x 104

cells/well onto a micropore polycarbonate insert of a 96

well plate (Merck, Millcell-96 culture insert plate 0.4

pm pore size, well membrane area = 0.11 cm 2 , PSHT004S5)

and cultured for 20 to 22 days, and the resulting

monolayer was used in the transcellular transport test.

The medium of the inoculated cells was replaced with a

fresh one every 3 to 4 days.

[0465] Apical-to-basolateral (A-to-B) transport in the

Caco2 cell monolayer membrane was performed by using HBSS

(Thermo Fisher Scientific, Inc., 14025) medium (pH = 7.4)

containing 20 mM HEPES (Thermo Fisher Scientific, Inc.,

15630), and adding HEPES-containing HBSS medium

containing 10 pM compound (a 10 mM solution of the

compound in DMSO was added at a 1000-fold dilution; final

DMSO concentration: 0.1%) at 75 pL/well to the apical

side and HEPES-containing HBSS medium supplemented with

no compound at 250 pL/well to the basolateral side,

followed by culture at 370C for 90 minutes. After

culture, a 100 pL aliquot was collected from the

basolateral side, and the concentration of a permeated

221102_G2572WO English Translation (Final) clean copy

compound was measured by LC-MS/MS under measurement

conditions mentioned later. Papp (apparent permeability;

cm/sec) was calculated from the determined concentration.

Papp was determined according to the expression given

below by calculating the slope (dA/dt; nmol/sec) of a

straight line drawn between two points 0 minutes and zero

amount of the compound in a graph plotted with an assay

time (90 min) on the abscissa against the amount of the

compound in the solution on the permeated side on the

ordinate. As for an assay concentration, the

concentration in the compound in the HEPES-containing

HBSS medium containing the added compound was measured by

UV-HPLC under measurement conditions mentioned later.

Papp (cm/sec) = CO x S x (dA / dt)

CO: assay concentration, S: plate membrane area =

0.11 cm 2

[0466] <Measurement conditions of LC-MS/MS analysis>

LC: LC20 or LC30 HPLC system manufactured by Shimadzu

Corp.

Column: Phenomenex Kinetex C18 (50 mm x 2.1 mm, 2.6

Pm)

Column temperature: 40 0 C

Flow rate: 0.3 mL/min

Mobile phase A: 0.1% aqueous formic acid solution

Mobile phase B: 0.1% formic acid, 50%

acetonitrile/methanol mixed solution

221102_G2572WO English Translation (Final) clean copy

Gradient: 0-2 min; A/B = 90/10 to 10/90, 2-3 min;

A/B = 10/90, 3-3.01 min; A/B = 10/90 to 90/10

MS: Q-Trap3200 manufactured by AB Sciex Pte. Ltd.

Ionization: ESI

Mode: Positive

[0467] <Measurement conditions of UV-HPLC analysis>

LC: LC20 or LC30 HPLC system manufactured by Shimadzu

Corp.

Column: Phenomenex Kinetex C18 (100 mm x 2.1 mm, 2.6

pm)

Column temperature: 40 0 C

Flow rate: 0.25 mL/min

Mobile phase A: 0.1% aqueous formic acid solution

Mobile phase B: 0.1% formic acid, 50%

acetonitrile/methanol mixed solution

Gradient: 0-3 min; A/B = 90/10, 3-11 min; A/B =

/10 to 5/95, 11-15 min; A/B = 5/95, 15-15.1 min; A/B =

/95 to 90/10

UV detector: photodiode array detector

[0468] The results about each test compound in this test

are shown in Table 22 below. A: Papp > 1 x 10-6 (cm/sec),

B: 1 x 10-6 (cm/sec) > Papp > 5 x 10-7 (cm/sec), C: 5 x 10

? (cm/sec) > Papp > 1 x 10-7 (cm/sec), or D: Papp < 1 x

-7 (cm/sec)

221102_G2572WO English Translation (Final) clean copy

Table 22. Results of transcellular transport test using Caco2 cell about compound of Example Example No. Papp Example No. Papp Example No. Papp 1-(b) A 21-(b) A 41-(b) A 2-(b) B 22-(b) A 42-(b) A 3-(b) A 23-(b) A 43-(b) A 4-(b) A 24-(b) B 44-(b) B -(b) B 25-(b) A 45-(b) B 6-(b) A 26-(b) A 46-(b) A 7-(b) B 27-(b) A 47-(b) A 8-(b) B 28-(b) A 48-(b) A 9-(b) A 29-(b) C 49-(b) B 10-(b) A 30-(b) B 50-(b) A 11-(b) A 31-(b) A 51-(b) A 12-(b) A 32-(b) A 52-(b) C 13-(b) A 33-(b) A 53-(b) C 14-(b) A 34-(b) A 54-(b) C 15-(b) A 35-(b) A 55-(b) C 16-(b) A 36-(b) A 56-(b) C 17-(b) A 37-(b) A 18-(b) A 38-(b) A 19-(b) A 39-(b) A 20-(b) A 40-(b) A

[0469] (Test Example 7) Dansyl glutathione (dGSH)

trapping assay

Among metabolites generated from a test compound

through metabolism in liver microsomes, a metabolite that

reacted with dansyl glutathione (dGSH) was detected and

quantified as a method for detecting a reactive

metabolite. The concentration of the metabolite-dGSH

conjugate was measured using fluorescence detection UPLC

system (manufactured by Shimadzu Corp.).

221102_G2572WO English Translation (Final) clean copy

As a result of testing compounds of Examples, the

compounds of Examples generated no or few dGSH adducts.

This demonstrated the compound represented by the general

formula (I) or (II) of the present invention or a

pharmaceutically acceptable salt thereof is a compound

excellent in safety that generates no or few reactive

metabolites.

[0470] (Test Example 8) Hepatic fibrosis suppression test

in carbon tetrachloride-induced hepatic fibrosis model

Carbon tetrachloride diluted 2-fold with olive oil

was subcutaneously administered at 2 mL/kg twice a week

up to the completion of a test to the back of C57BL/6J

mice (female, Charles River Laboratories Japan, Inc.)

under inhalation anesthesia with isoflurane to prepare

carbon tetrachloride-induced hepatic fibrosis models. A

test compound was orally administered once a day for 56

days from the start of model preparation. Then, the

liver was collected, and HYP in the left lateral hepatic

lobe was quantified.

As a result of testing compounds of Examples, the

compounds of Examples suppressed increase in HYP.

[0471] (Test Example 9) Pulmonary fibrosis suppression

test in bleomycin-induced idiopathic pulmonary fibrosis

model

Bleomycin (manufactured by Nippon Kayaku Co., Ltd.)

diluted with physiological saline was transtracheally

administered once at 3.0 mg/kg (50 pL/animal) to C57BL/6J

221102_G2572WO English Translation (Final) clean copy

mice (female, Japan SLC, Inc.) under triple anesthesia

(medetomidine hydrochloride/midazolam/butorphanol

tartrate) using Microsprayer (manufactured by Penn

Century, Inc.) to prepare bleomycin-induced idiopathic

pulmonary fibrosis models. A test compound was

administered thereto for 14 days from 7 days after

bleomycin administration. Then, the lung was collected,

and HYP was quantified using the pulmonary left lobe.

As a result of testing compounds of Examples, the

compounds of Examples suppressed increase in HYP.

[0472] (Test Example 10) Renal fibrosis suppression test

in unilateral ureteral obstruction model with renal

fibrosis

Test Example 10 was performed with reference to the

method of Swaney et al. (The Journal of Pharmacology and

Experimental Therapeutics 336 (3): 693-700 (2011)). The

left ureter of C57BL/6J mice (male, Japan SLC, Inc.) was

ligated with a suture thread under inhalation anesthesia

with isoflurane to prepare unilateral ureteral

obstruction models with renal fibrosis. A test compound

was administered thereto for 10 days from model

preparation. Then, the left kidney was collected, and

HYP was quantified.

As a result of testing compounds of Examples, the

compounds of Examples suppressed increase in HYP.

Claims (16)

1. Claims

   [Claim 1]

   A compound represented by the following general

   formula (I) or (II) or a pharmaceutically acceptable salt

   thereof:

   Y Y

   HN N HN N O H Y H HN N CO2R HN N CO2R I / 0 A O 0 A R 1/: R1 N-NH HN-N

   (I) (II) wherein

   A is a C 6 -C1 0 aryl group or a heteroaryl group,

   wherein at least one hydrogen atom of the aryl group or

   the heteroaryl group is optionally replaced with a

   substituent selected from the group consisting of a

   halogen atom, a hydroxy group, a C 1 -C6 alkyl group, a C1

   C 6 haloalkyl group, a C 2 -C 6 alkenyl group, a C 2 -C 6 alkynyl

   group, a C 1 -C 6 alkoxy group, a C 1 -C 6 haloalkoxy group, a

   C 3 -C 6 cycloalkyl group, a C 3 -C 6 cycloalkenyl group, a C 3 -C 6

   cycloalkoxy group, a heterocyclyl group, a heteroaryl

   group optionally substituted by a C 1 -C 6 alkyl group, a

   cyano group, a carboxyl group, a carbamoyl group, a C 1 -C6

   alkoxycarbonyl group, a C1 -C 6 alkylsulfanyl group, and a

   C1 -C 6 alkylsulfonyl group,

   R is a hydrogen atom or a C 1 -C6 alkyl group,

   R' is a hydrogen atom or a halogen atom, and

   Y is a hydrogen atom, a fluorine atom or a hydroxy

   group.
2. [Claim 2]

   A compound represented by the following general

   formula (I) or a pharmaceutically acceptable salt

   thereof:

   Y

   HN N HN O N N CO 2 R

   R 1 1 H0 A N-NH

   (I) wherein

   A is a C6-C10 aryl group or a heteroaryl group,

   wherein at least one hydrogen atom of the aryl group or

   the heteroaryl group is optionally replaced with a

   substituent selected from the group consisting of a

   halogen atom, a hydroxy group, a C1-C6 alkyl group, a C1

   C6 haloalkyl group, a C2-C6 alkenyl group, a C2-C6 alkynyl

   group, a C1-C6 alkoxy group, a C1-C6 haloalkoxy group, a

   C3-C6 cycloalkyl group, a C3-C6 cycloalkenyl group, a C3-C6

   cycloalkoxy group, a heterocyclyl group, a heteroaryl

   group optionally substituted by a C1-C6 alkyl group, a

   cyano group, a carboxyl group, a carbamoyl group, a C1-C6

   alkoxycarbonyl group, a C1-C6 alkylsulfanyl group, and a

   C1-C6 alkylsulfonyl group,

   R is a hydrogen atom or a C1-C6 alkyl group,

   R' is a hydrogen atom or a halogen atom, and

   Y is a hydrogen atom, a fluorine atom or a hydroxy

   group.
3. [Claim 3]

   A compound represented by the following general

   formula (II) or a pharmaceutically acceptable salt

   thereof:

   Y

   HN N HN N CO2R 0 O A R1 HN-N

   (10)

   wherein

   A is a C6-C1O aryl group or a heteroaryl group,

   wherein at least one hydrogen atom of the aryl group or

   the heteroaryl group is optionally replaced with a

   substituent selected from the group consisting of a

   halogen atom, a hydroxy group, a C1-C6 alkyl group, a C1

   C6 haloalkyl group, a C2-C6 alkenyl group, a C2-C6 alkynyl

   group, a C1-C6 alkoxy group, a C1-C6 haloalkoxy group, a

   C3-C6 cycloalkyl group, a C3-C6 cycloalkenyl group, a C3-C6

   cycloalkoxy group, a heterocyclyl group, a heteroaryl

   group optionally substituted by a C1-C6 alkyl group, a

   cyano group, a carboxyl group, a carbamoyl group, a C1-C6 alkoxycarbonyl group, a C1-C6 alkylsulfanyl group, and a

   C1-C6 alkylsulfonyl group,

   R is a hydrogen atom or a C1-C alkyl group,

   R' is a hydrogen atom or a halogen atom, and

   Y is a hydrogen atom, a fluorine atom or a hydroxy

   group.
4. [Claim 4]

   The compound according to any one of claims 1 to 3

   or a pharmaceutically acceptable salt thereof, wherein A

   is a phenyl group, wherein

   at least one hydrogen atom of the phenyl group is

   optionally replaced with a substituent selected from the

   group consisting of a halogen atom, a hydroxy group, a

   C1-C6 alkyl group, a C1-C6 haloalkyl group, a C2-C6 alkenyl

   group, a C2-C6 alkynyl group, a C1-C6 alkoxy group, a C1-C6

   haloalkoxy group, a C3-C6 cycloalkyl group, a C3-C6

   cycloalkenyl group, a C3-C6 cycloalkoxy group, a

   heterocyclyl group, a heteroaryl group optionally

   substituted by a C1-C6 alkyl group, a cyano group, a

   carboxyl group, a carbamoyl group, a C1-C6 alkoxycarbonyl

   group, a C1-C6 alkylsulfanyl group, and a C1-C6

   alkylsulfonyl group.
5. [Claim 5]

   The compound according to any one of claims 1 to 4

   or a pharmaceutically acceptable salt thereof, wherein A

   is a phenyl group, wherein at least one hydrogen atom of the phenyl group is optionally replaced with a substituent selected from the group consisting of a halogen atom, a C1-C6 alkyl group, a C1-C6 haloalkyl group, a C1-C6 alkoxy group, a C1-C6 haloalkoxy group, a C3-C6 cycloalkyl group, a C3-C6 cycloalkoxy group, a heterocyclyl group, and a heteroaryl group optionally substituted by a C1-C6 alkyl group.
6. [Claim 6]

   The compound according to any one of claims 1 to 5

   or a pharmaceutically acceptable salt thereof, wherein Y

   is a fluorine atom.
7. [Claim 7]

   The compound according to any one of claims 1 to 6

   or a pharmaceutically acceptable salt thereof, wherein A

   is a group represented by the following formula (i):

   RS6 R2

   R5 / R3 R4

   0) wherein

   R 2 is a hydrogen atom or a halogen atom,

   R 3 is a hydrogen atom, a halogen atom, a C1-C6 alkyl

   group, a C1-C6 haloalkyl group, a C1-C6 alkoxy group, a

   C1-C6 haloalkoxy group, a C3-C6 cycloalkyl group, a C3-C6

   cycloalkoxy group, a heterocyclyl group, or a heteroaryl

   group optionally substituted by a C1-C6 alkyl group,

   R4 is a hydrogen atom, a halogen atom, a C1-C6 alkyl

   group, a C1-C6 haloalkyl group, a C1-C6 alkoxy group, or a

   C1-C6 haloalkoxy group,

   R5 is a hydrogen atom, a halogen atom, a C1-C6 alkyl

   group, a C1-C6 haloalkyl group, a C1-C6 alkoxy group, a

   C1-C6 haloalkoxy group, or a heteroaryl group optionally

   substituted by a C1-C6 alkyl group, and

   R 6 is a hydrogen atom or a halogen atom.
8. [Claim 8]

   The compound according to claim 7 or a

   pharmaceutically acceptable salt thereof, wherein

   R 2 is a hydrogen atom,

   R 3 is a hydrogen atom, a halogen atom, a C1-C6 alkyl

   group, a C1-C6 haloalkyl group, a C1-C6 alkoxy group, a

   C1-C6 haloalkoxy group, or a heteroaryl group optionally

   substituted by a C1-C6 alkyl group,

   R 4 is a hydrogen atom or a halogen atom,

   R5 is a hydrogen atom, a halogen atom, a C1-C6 alkyl

   group, a C1-C6 haloalkyl group, a C1-C6 alkoxy group, or a

   C1-C6 haloalkoxy group, and

   R 6 is a hydrogen atom or a halogen atom.
9. [Claim 9]

   The compound according to claim 1 or a

   pharmaceutically acceptable salt thereof, wherein the

   compound is selected from the group consisting of

   (3S)-3-(3-chloro-5-(trifluoromethyl)phenyl)-3-(2-(4

   ((5-fluoro-1,4,5,6-tetrahydropyrimidin-2-yl)amino)-1H

   indazole-6-carboxamido)acetamido)propanoic acid,

   (3S)-3-(3-bromo-5-(trifluoromethyl)phenyl)-3-(2-(4

   ((5-fluoro-1,4,5,6-tetrahydropyrimidin-2-yl)amino)-1H

   indazole-6-carboxamido)acetamido)propanoic acid,

   (3S)-3-(2-(4-((5-fluoro-1,4,5,6-tetrahydropyrimidin

   2-yl)amino)-1H-indazole-6-carboxamido)acetamido)-3-(3

   iodo-5-(trifluoromethyl)phenyl)propanoic acid,

   (3S)-3-(2-(4-((5-fluoro-1,4,5,6-tetrahydropyrimidin

   2-yl)amino)-1H-indazole-6-carboxamido)acetamido)-3-(3

   methyl-5-(trifluoromethyl)phenyl)propanoic acid,

   (3S)-3-(2-(4-((5-fluoro-1,4,5,6-tetrahydropyrimidin

   2-yl)amino)-1H-indazole-6-carboxamido)acetamido)-3-(3

   methoxy-5-(trifluoromethyl)phenyl)propanoic acid,

   (3S)-3-(2-(4-((5-fluoro-1,4,5,6-tetrahydropyrimidin

   2-yl)amino)-1H-indazole-6-carboxamido)acetamido)-3-(3

   fluoro-5-(trifluoromethyl)phenyl)propanoic acid,

   (3S)-3-(3,5-bis(trifluoromethyl)phenyl)-3-(2-(4-((5

   fluoro-1,4,5,6-tetrahydropyrimidin-2-yl)amino)-1H

   indazole-6-carboxamido)acetamido)propanoic acid,

   (3S)-3-(3-(1H-pyrazol-1-yl)-5

   (trifluoromethyl)phenyl)-3-(2-(4-((5-fluoro-1,4,5,6

   tetrahydropyrimidin-2-yl)amino)-1H-indazole-6

   carboxamido)acetamido)propanoic acid,

   (3S)-3-(2-(4-((5-fluoro-1,4,5,6-tetrahydropyrimidin

   2-yl)amino)-1H-indazole-6-carboxamido)acetamido)-3-(2

   fluoro-3-(trifluoromethyl)phenyl)propanoic acid,

   (3S)-3-(2-chloro-3-(trifluoromethyl)phenyl)-3-(2-(4

   ((5-fluoro-1,4,5,6-tetrahydropyrimidin-2-yl)amino)-1H

   indazole-6-carboxamido)acetamido)propanoic acid,

   (3S)-3-(2-(4-((5-fluoro-1,4,5,6-tetrahydropyrimidin

   2-yl)amino)-1H-indazole-6-carboxamido)acetamido)-3-(2

   fluoro-5-(trifluoromethyl)phenyl)propanoic acid,

   (3S)-3-(2-chloro-5-(trifluoromethyl)phenyl)-3-(2-(4

   ((5-fluoro-1,4,5,6-tetrahydropyrimidin-2-yl)amino)-1H

   indazole-6-carboxamido)acetamido)propanoic acid,

   (3S)-3-(2-(4-((5-fluoro-1,4,5,6-tetrahydropyrimidin

   2-yl)amino)-1H-indazole-6-carboxamido)acetamido)-3-(4

   fluoro-3-(trifluoromethyl)phenyl)propanoic acid,

   (3S)-3-(2-(4-((5-fluoro-1,4,5,6-tetrahydropyrimidin

   2-yl)amino)-1H-indazole-6-carboxamido)acetamido)-3-(4

   methyl-3-(trifluoromethyl)phenyl)propanoic acid,

   (3S)-3-(3-chloro-4-fluoro-5

   (trifluoromethyl)phenyl)-3-(2-(4-((5-fluoro-1,4,5,6

   tetrahydropyrimidin-2-yl)amino)-1H-indazole-6

   carboxamido)acetamido)propanoic acid,

   (3S)-3-(3-bromo-4-methoxyphenyl)-3-(2-(4-((5-fluoro

   1,4,5,6-tetrahydropyrimidin-2-yl)amino)-1H-indazole-6

   carboxamido)acetamido)propanoic acid,

   (3S)-3-(3,5-dichlorophenyl)-3-(2-(4-((5-fluoro

   1,4,5,6-tetrahydropyrimidin-2-yl)amino)-1H-indazole-6

   carboxamido)acetamido)propanoic acid,

   (3S)-3-(3-bromo-5-chlorophenyl)-3-(2-(4-((5-fluoro

   1,4,5,6-tetrahydropyrimidin-2-yl)amino)-1H-indazole-6

   carboxamido)acetamido)propanoic acid,

   (3S)-3-(3,5-dibromophenyl)-3-(2-(4-((5-fluoro

   1,4,5,6-tetrahydropyrimidin-2-yl)amino)-1H-indazole-6

   carboxamido)acetamido)propanoic acid,

   (3S)-3-(3-bromo-5-iodophenyl)-3-(2-(4-((5-fluoro

   1,4,5,6-tetrahydropyrimidin-2-yl)amino)-1H-indazole-6

   carboxamido)acetamido)propanoic acid,

   (3S)-3-(3-chloro-5-iodophenyl)-3-(2-(4-((5-fluoro

   1,4,5,6-tetrahydropyrimidin-2-yl)amino)-1H-indazole-6

   carboxamido)acetamido)propanoic acid,

   (3S)-3-(5-chloro-2-fluorophenyl)-3-(2-(4-((5-fluoro

   1,4,5,6-tetrahydropyrimidin-2-yl)amino)-1H-indazole-6

   carboxamido)acetamido)propanoic acid,

   (3S)-3-(5-bromo-2-fluorophenyl)-3-(2-(4-((5-fluoro

   1,4,5,6-tetrahydropyrimidin-2-yl)amino)-1H-indazole-6

   carboxamido)acetamido)propanoic acid,

   (3S)-3-(3-(difluoromethoxy)-5

   (trifluoromethyl)phenyl)-3-(2-(4-((5-fluoro-1,4,5,6

   tetrahydropyrimidin-2-yl)amino)-1H-indazole-6

   carboxamido)acetamido)propanoic acid,

   (3S)-3-(3-chloro-5-(difluoromethoxy)phenyl)-3-(2-(4

   ((5-fluoro-1,4,5,6-tetrahydropyrimidin-2-yl)amino)-1H

   indazole-6-carboxamido)acetamido)propanoic acid,

   (3S)-3-(3-bromo-5-(difluoromethoxy)phenyl)-3-(2-(4

   ((5-fluoro-1,4,5,6-tetrahydropyrimidin-2-yl)amino)-1H

   indazole-6-carboxamido)acetamido)propanoic acid,

   (3S)-3-(3-(difluoromethoxy)-4-fluorophenyl)-3-(2-(4

   ((5-fluoro-1,4,5,6-tetrahydropyrimidin-2-yl)amino)-1H

   indazole-6-carboxamido)acetamido)propanoic acid,

   (3S)-3-(5-(difluoromethoxy)-2-fluorophenyl)-3-(2-(4

   ((5-fluoro-1,4,5,6-tetrahydropyrimidin-2-yl)amino)-1H

   indazole-6-carboxamido)acetamido)propanoic acid,

   (3S)-3-(3-(difluoromethoxy)-5-(1H-pyrazol-1

   yl)phenyl)-3-(2-(4-((5-fluoro-1,4,5,6

   tetrahydropyrimidin-2-yl)amino)-1H-indazole-6

   carboxamido)acetamido)propanoic acid,

   (3S)-3-(3,5-bis(difluoromethoxy)phenyl)-3-(2-(4-((5

   fluoro-1,4,5,6-tetrahydropyrimidin-2-yl)amino)-1H

   indazole-6-carboxamido)acetamido)propanoic acid,

   (3S)-3-(3-chloro-5-(trifluoromethoxy)phenyl)-3-(2

   (4-((5-fluoro-1,4,5,6-tetrahydropyrimidin-2-yl)amino)-1H

   indazole-6-carboxamido)acetamido)propanoic acid,

   (3S)-3-(3-bromo-5-(trifluoromethoxy)phenyl)-3-(2-(4

   ((5-fluoro-1,4,5,6-tetrahydropyrimidin-2-yl)amino)-1H

   indazole-6-carboxamido)acetamido)propanoic acid,

   (3S)-3-(2-(4-((5-fluoro-1,4,5,6-tetrahydropyrimidin

   2-yl)amino)-1H-indazole-6-carboxamido)acetamido)-3-(2

   fluoro-5-(trifluoromethoxy)phenyl)propanoic acid,

   (3S)-3-(2-(4-((5-fluoro-1,4,5,6-tetrahydropyrimidin

   2-yl)amino)-1H-indazole-6-carboxamido)acetamido)-3-(4

   fluoro-3-(trifluoromethoxy)phenyl)propanoic acid,

   (3S)-3-(2-(4-((5-fluoro-1,4,5,6-tetrahydropyrimidin

   2-yl)amino)-1H-indazole-6-carboxamido)acetamido)-3-(3

   (trifluoromethyl)phenyl)propanoic acid,

   (3S)-3-(2-(4-((5-fluoro-1,4,5,6-tetrahydropyrimidin

   2-yl)amino)-1H-indazole-6-carboxamido)acetamido)-3-(3

   (trifluoromethoxy)phenyl)propanoic acid,

   (3S)-3-(3-(difluoromethoxy)phenyl)-3-(2-(4-((5

   fluoro-1,4,5,6-tetrahydropyrimidin-2-yl)amino)-1H

   indazole-6-carboxamido)acetamido)propanoic acid,

   (3S)-3-(3-(difluoromethyl)phenyl)-3-(2-(4-((5

   fluoro-1,4,5,6-tetrahydropyrimidin-2-yl)amino)-1H

   indazole-6-carboxamido)acetamido)propanoic acid,

   (3S)-3-(3-cyclopropylphenyl)-3-(2-(4-((5-fluoro

   1,4,5,6-tetrahydropyrimidin-2-yl)amino)-1H-indazole-6

   carboxamido)acetamido)propanoic acid,

   (3S)-3-(3-cyclopropoxyphenyl)-3-(2-(4-((5-fluoro

   1,4,5,6-tetrahydropyrimidin-2-yl)amino)-1H-indazole-6

   carboxamido)acetamido)propanoic acid,

   (3S)-3-(3-chlorophenyl)-3-(2-(4-((5-fluoro-1,4,5,6

   tetrahydropyrimidin-2-yl)amino)-1H-indazole-6

   carboxamido)acetamido)propanoic acid,

   (3S)-3-(3-bromophenyl)-3-(2-(4-((5-fluoro-1,4,5,6

   tetrahydropyrimidin-2-yl)amino)-1H-indazole-6

   carboxamido)acetamido)propanoic acid,

   (3S)-3-(3-(1H-pyrazol-1-yl)phenyl)-3-(2-(4-((5

   fluoro-1,4,5,6-tetrahydropyrimidin-2-yl)amino)-1H

   indazole-6-carboxamido)acetamido)propanoic acid,

   (3S)-3-(3-(3,5-dimethyl-1H-pyrazol-1-yl)phenyl)-3

   (2-(4-((5-fluoro-1,4,5,6-tetrahydropyrimidin-2-yl)amino)

   1H-indazole-6-carboxamido)acetamido)propanoic acid,

   (3S)-3-(2-(4-((5-fluoro-1,4,5,6-tetrahydropyrimidin

   2-yl)amino)-1H-indazole-6-carboxamido)acetamido)-3-(3

   morpholinophenyl)propanoic acid,

   (3S)-3-(4-(difluoromethoxy)phenyl)-3-(2-(4-((5

   fluoro-1,4,5,6-tetrahydropyrimidin-2-yl)amino)-1H

   indazole-6-carboxamido)acetamido)propanoic acid,

   (3S)-3-(2-(4-((5-fluoro-1,4,5,6-tetrahydropyrimidin

   2-yl)amino)-1H-indazole-6-carboxamido)acetamido)-3-(4

   (trifluoromethyl)phenyl)propanoic acid,

   (3S)-3-(3-chloro-5-(trifluoromethyl)phenyl)-3-(2-(3

   fluoro-4-((5-fluoro-1,4,5,6-tetrahydropyrimidin-2

   yl)amino)-1H-indazole-6-carboxamido)acetamido)propanoic

   acid,

   (3S)-3-(2-(3-chloro-4-((5-fluoro-1,4,5,6

   tetrahydropyrimidin-2-yl)amino)-1H-indazole-6

   carboxamido)acetamido)-3-(3-chloro-5

   (trifluoromethyl)phenyl)propanoic acid,

   (3S)-3-(3-chloro-5-(trifluoromethyl)phenyl)-3-(2-(4

   ((5-hydroxy-1,4,5,6-tetrahydropyrimidin-2-yl)amino)-1H

   indazole-6-carboxamido)acetamido)propanoic acid,

   (S)-3-(3-chloro-5-(trifluoromethyl)phenyl)-3-(2-(4

   ((1,4,5,6-tetrahydropyrimidin-2-yl)amino)-1H-indazole-6

   carboxamido)acetamido)propanoic acid,

   (3S)-3-(3-chloro-5-(trifluoromethyl)phenyl)-3-(2-(6

   ((5-fluoro-1,4,5,6-tetrahydropyrimidin-2-yl)amino)-1H

   indazole-4-carboxamido)acetamido)propanoic acid,

   (3S)-3-(3-bromo-5-(trifluoromethyl)phenyl)-3-(2-(6

   ((5-fluoro-1,4,5,6-tetrahydropyrimidin-2-yl)amino)-1H

   indazole-4-carboxamido)acetamido)propanoic acid,

   (3S)-3-(2-(6-((5-fluoro-1,4,5,6-tetrahydropyrimidin

   2-yl)amino)-1H-indazole-4-carboxamido)acetamido)-3-(3

   iodo-5-(trifluoromethyl)phenyl)propanoic acid,

   (3S)-3-(2-(6-((5-fluoro-1,4,5,6-tetrahydropyrimidin

   2-yl)amino)-1H-indazole-4-carboxamido)acetamido)-3-(4

   fluoro-3-(trifluoromethyl)phenyl)propanoic acid, and

   (3S)-3-(2-(6-((5-fluoro-1,4,5,6-tetrahydropyrimidin

   2-yl)amino)-1H-indazole-4-carboxamido)acetamido)-3-(3

   (trifluoromethyl)phenyl)propanoic acid.
10. [Claim 10]

    A pharmaceutical composition comprising a compound

    according to any one of claims 1 to 9 or a

    pharmaceutically acceptable salt thereof.
11. [Claim 11]

    The pharmaceutical composition according to claim 10

    for preventing, alleviating and/or treating a disease

    related to integrin av or a disease that is improved by

    inhibiting integrin av.
12. [Claim 12]

    The pharmaceutical composition according to claim 9

    or 10 for the remedy of fibrosis.
13. [Claim 13]

    A method for preventing, alleviating and/or treating

    a disease related to integrin av or a disease that is

    improved by inhibiting integrin av, comprising

    administering a compound according to any one of claims 1

    to 9 or a pharmaceutically acceptable salt thereof to a

    subject.
14. [Claim 14]

    A method for treating fibrosis, comprising

    administering a compound according to any one of claims 1

    to 9 or a pharmaceutically acceptable salt thereof to a

    subject.
15. [Claim 15]

    The compound according to any one of claims 1 to 9

    or a pharmaceutically acceptable salt thereof for use in

    the prevention, alleviation and/or remedy of a disease

    related to integrin av or a disease that is improved by

    inhibiting integrin av.
16. [Claim 16]

    The compound according to any one of claims 1 to 9

    or a pharmaceutically acceptable salt thereof for use in

    the remedy of fibrosis.